Luminescent polydentate polycyclic compounds for metal ions

ABSTRACT

Polydentate polycyclic compounds of various formulas are disclosed herein. The compounds are useful for ratiometric luminescence. Significantly, the compounds will luminesce at different wavelengths/colors, depending on the analyte (metal ion, acid, or boron-containing compound) it is combined with. Thus, a single compound can provide different luminescent outputs based on the analyte, rather than requiring an entire set of structurally different compounds to detect each analyte or to generate a desired color output.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 61/694,581, filed on Aug. 29, 2012. That application is herebyincorporated by reference in its entirety.

BACKGROUND

The present disclosure relates to various polydentate polycycliccompounds whose luminescent properties change when combined with ananalyte. These compounds may be useful in light-emitting applications,metal ion detection or recognition, metal ion extraction, catalysis,development of shape-persistent macrocycles, and/or assembly of metalorganic frameworks.

Luminescence is the emission of light by a substance/material that doesnot result from heat. Examples of luminescence include fluorescence andphosphorescence. Fluorescence occurs when a substance/material absorbsultraviolet (UV) light, and then emits light, typically of a lowerwavelength. This phenomenon can be useful in many applications. Forexample, in biochemistry, an antibody can be labeled with a fluorophore.The antibody will attach to its target antigen, and the fluorescence ofthe fluorophore can be detected to identify the location of the targetantigen. Labelling multiple antibodies with different fluorophoresallows visualization of multiple target antigens. For example, onefluorophore can emit a red color, a second fluorophore can emit a bluecolor, and a third fluorophore can emit a green color. In fluorescence,the re-emission of light occurs relatively quickly (nanoseconds),whereas in phosphorescence the re-emission of light occurs relativelyslowly (milliseconds to hours).

Generally, a structurally different compound is needed for eachdifferent color. As a result, an entire set of structurally differentcompounds are needed in order to obtain different luminescent outputs.It would be desirable to be able to reduce the number of compoundsneeded to generate the same number of different luminescent outputs.

BRIEF DESCRIPTION

The present disclosure relates to various compounds or receptors thatcan generate different luminescent colors upon exposure to differentanalytes. Generally speaking, the compounds of the present disclosureincorporate the structural properties of 8-hydroxyquinoline to form apolydentate polycyclic compound. The compounds interact with analytessuch as metal ions, acids, or boron-containing compounds, and luminesceat different wavelengths depending upon the analyte. This can be usefulin applications such as metal ion extraction, metal ion detection,organic light emitting diodes, magnetic resonance imaging (MRI) contrastagents, catalysts, and the generation of storage devices such asmetal-organic frameworks.

Disclosed in various embodiments herein is a compound having thestructure of Formula (S1), or a polymer formed from a monomer having thestructure of Formula (S1):

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂ areindependently selected from hydrogen, halogen, alkyl, substituted alkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, hydroxyl, aldehyde,carboxy, ester, sulfonate, sulfonamide, carboxamide, amino, nitro,nitroso, nitrile, azo, and a water-solubilizing group;wherein one of R₁ to R₅ is —OR′, —SR′, or —NR′₂;one of R₈ to R₁₂ is —OR″, —SR″, or —NR″₂; andwherein R′ and R″ are independently selected from hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, or a chelating ligand comprising at least one linking groupand at least one heteroatom, or together form a linking moiety thatcontains at least one heteroatom, so that the compound is a macrocycliccompound.

In some particular embodiments of (S1), R′ and R″ are each a chelatingligand, and each chelating ligand is selected from —CO—R,—(CH₂)_(n)—CO—OR, —(CH₂)n-CO—NR¹R², —(CH₂)_(n)—Z—(CH₂)_(m)—CO—OR,—(CH₂)_(n)—NR³—(CH₂)_(m)—CO—OR, —(CH₂)_(n)—[O—(CH₂)_(k)]_(m)—OR, orsalts thereof; wherein k, m, and n are independently integers from 0 to10; R, R¹, R², and R³ are independently hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;and Z is sulfur or oxygen. R′ and R″ can be the same.

In particular embodiments, R₄ and R₉ are the same, and are not hydrogen.In others, R₄ and R₉ are halogen, aryl, substituted aryl, alkynyl, orsubstituted alkynyl.

The compound of Formula (S1) may have the structure of one of formulas(D1)-(D9), as described further herein. The compound of Formula (S1) maybe a macrocyclic compound having the structure of Formula (S1-M) orFormulas (M1)-(M7) as described further herein.

Also disclosed are methods for making a compound of Formula (S1),comprising: reacting a 1,2-cyclohexanedione of Formula (S1a) with afirst aminoaldehyde; and optionally, when R′ and R″ are different,reacting the resulting compound with a second different aminoaldehyde.

The reacting may occur in the presence of potassium hydroxide andethanol until the aminoaldehyde is consumed, wherein trifluoroaceticacid is subsequently added to precipitate the compound of Formula (S1).

In particular embodiments, the method may further comprise: reducing theresulting compound with hydrobromic acid to form adihydroxy-3,3′-dimethylene-2,2′-biquinoline; reacting thedihydroxy-3,3′-dimethylene-2,2′-biquinoline with a first reactant of theformula L^(a)-R′, wherein L^(a) is a leaving group; and wherein R′ andR″ are different, reacting the resulting compound with a second reactantof the formula L^(b)-R″, wherein L^(b) is a leaving group.

The reacting of the dihydroxy-3,3′-dimethylene-2,2′-biquinoline with thefirst and second reactants can occur in the presence of a polar solvent.

Also disclosed herein are methods for binding a metal ion in a solution,comprising: adding to the solution a compound having the structure ofFormula (S1), or a polymer formed from a monomer having the structure ofFormula (S1), wherein the compound or polymer forms a complex uponbinding to the metal ion.

Sometimes, the methods further comprise monitoring the solution todetect a change in the color of light emitted by the compound orpolymer, such a change indicating that binding has occurred. The methodscan also further comprise extracting the complex from the solution.

Also disclosed herein are compounds having the structure of Formula(S2):

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂ areindependently selected from hydrogen, halogen, alkyl, substituted alkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, hydroxyl, aldehyde,carboxy, ester, sulfonate, sulfonamide, carboxamide, amino, nitro,nitroso, nitrile, azo, and a water-solubilizing group;wherein one of R₁ to R₅ is —OR′, —SR′, or —NR′₂;one of R₈ to R₁₂ is —OR″, —SR″, or —NR″₂; andwherein R′ and R″ are independently selected from hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, or a chelating ligand comprising at least one linking groupand at least one heteroatom, or together form a linking moiety thatcontains at least one heteroatom, so that the compound is a macrocycliccompound.

Also disclosed herein are compounds having the structure of Formula(S3):

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, andR₁₅ are independently selected from hydrogen, halogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,hydroxyl, aldehyde, carboxy, ester, sulfonate, sulfonamide, carboxamide,amino, nitro, nitroso, nitrile, azo, and a water-solubilizing group;wherein one of R₁ to R₅ is —OR′, —SR′, or —NR′″₂;one of R₁₁ to R₁₅ is —OR″, —SR″, or —NR″″₂;wherein R′ and R″ are independently a chelating ligand comprising atleast one linking group and at least one heteroatom, or together form alinking moiety that contains at least one heteroatom, so that thecompound is a macrocyclic compound; andwherein R′″ and R″″ are independently hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aldehyde,carboxy, ester, or a chelating ligand comprising at least one linkinggroup and at least one heteroatom, or together form a linking moietythat contains at least one heteroatom, so that the compound is amacrocyclic compound.

Also disclosed herein are compounds having the structure of Formula(S4):

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄,R₁₅, R₁₆, R₁₇, R₁₈, and R₁₉ are independently selected from hydrogen,halogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, hydroxyl, aldehyde, carboxy, ester, sulfonate,sulfonamide, carboxamide, amino, nitro, nitroso, nitrile, azo, and awater-solubilizing group;wherein one of R₁ to R₅ is —OR′, —SR′, or —NR′″₂;one of R₁₅ to R₁₉ is —OR″, —SR″, or —NR″″₂;wherein R′ and R″ are independently a chelating ligand comprising atleast one linking group and at least one heteroatom, or together form alinking moiety that contains at least one heteroatom, so that thecompound is a macrocyclic compound; andwherein R′″ and R″″ are independently hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aldehyde,carboxy, ester, or a chelating ligand comprising at least one linkinggroup and at least one heteroatom, or together form a linking moietythat contains at least one heteroatom, so that the compound is amacrocyclic compound.

Sometimes, in Formula (S2), (S3), or (S4), R′ and R″ are each achelating ligand, and each chelating ligand is selected from —CO—R,—(CH₂)_(n)—CO—OR, —(CH₂)n-CO—NR¹R², —(CH₂)_(n)—Z—(CH₂)_(m)—CO—OR,—(CH₂)_(n)—NR³—(CH₂)_(m)—CO—OR, —(CH₂)_(n)—[O—(CH₂)_(k)]_(m)—OR, orsalts thereof; wherein k, m, and n are independently integers from 0 to10; R, R¹, R², and R³ are independently hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;and Z is sulfur or oxygen.

Sometimes, the compound of Formula (S3) has the structure of one offormulas L1, L2, or L3, as described further herein. Sometimes, thecompound of Formula (S4) has the structure of formula L4 as describedfurther herein.

These and other non-limiting characteristics are more particularlydescribed below.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

The following is a brief description of the drawings, which arepresented for the purposes of illustrating the exemplary embodimentsdisclosed herein and not for the purposes of limiting the same.

FIG. 1 is a set of pictures showing the change in color of derivativecompound D1 in the absence and presence of various metal ions (Mg²⁺,Sr²⁺, Ca²⁺, Cd²⁺, Zn²⁺, H⁺) in solution. The solvent was acetonitrile,the concentration of D1 was 0.004 M, and the metal ion concentration was0.04 M. The metal ions are added as perchlorates or acetates. Thesolutions were exposed to UV light having an excitation wavelength of365 nm.

FIG. 2 is a set of pictures showing the change in color of derivativecompound D1 in the absence and presence of various metal ions (Ca²⁺,Sr²⁺, Cd²⁺, Zn²⁺, Ba²⁺, K⁺, H⁺, Ni²⁺) in the solid state.

FIG. 3 shows the normalized emission spectra of D1 and some of thecomplexes in water-saturated acetonitrile. The concentration of D1 was0.004 M, and the metal ion concentration was 0.04 M. The metal ions areadded as perchlorates or acetates. The solutions were exposed to UVlight having an excitation wavelength of 285 nm or larger. From left toright, the legend reads: K⁺, Mg²⁺, Sr²⁺, Ca²⁺, Cd²⁺, Zn²⁺.

FIG. 4 is a set of pictures showing the change in color of derivativecompound D1 in the absence and presence of various metal ions (Ca²⁺,Zn²⁺, Al³⁺, Pb²⁺) in solution, both under ordinary light and under UVlight (365 nm). The solvent was acetonitrile, the concentration of D1was 0.0001 M, and one equivalent of the metal perchlorate salt wasadded.

FIG. 5 is a set of pictures showing the change in color of derivativecompound D1 in the absence and presence of various metal ions or acids(Ca²⁺, Zn²⁺, Al³⁺, Pb²⁺) in the solid state, both under ordinary lightand under UV light (365 nm).

FIG. 6 is a set of pictures showing the change in color of derivativecompound D1 in the absence and presence of various metal ions or acids(La³⁺, Co²⁺, Ni²⁺, Cu²⁺) in the solid state, both under ordinary lightand under UV light (365 nm).

FIG. 7 is a set of pictures showing the change in color of derivativecompound D1 in the absence and presence of various metal ions or acids(AgNO₃, Hg²⁺, Pb²⁺) and of the free compound D7 (no metal ion) in thesolid state, both under ordinary light and under UV light (365 nm).

FIG. 8 is a set of pictures showing the fluorescent properties ofcompound L4 in two different solvents (water and chloroform) in thepresence of different metal ions o and acid (NaCl, CaCl₂, HCl) underordinary light and under UV light (365 nm). The concentration of L4 was0.00032 M. Vial #2 used aqueous sodium chloride, Vial #3 includedaqueous calcium chloride, and Vial #4 included dilute hydrochloric acid.

FIG. 9 shows the X-ray crystal structure of the complex D1.AgClO₄.CH₃CN.This is a 1:1 complex (ligand:metal).

FIG. 10 shows the X-ray crystal structure of the complex D1.Ca(ClO₄)₂.This is a 1:1 complex (ligand:metal). Portions of additional perchlorateions belonging to a nearby complex (not shown) also appear.

FIG. 11 shows the X-ray crystal structure of the complex(D1)₂.Zn(ClO₄)₂. This is a 2:1 (ligand:metal) encapsulating complex. Theperchlorate ions have been omitted.

FIG. 12 shows the X-ray crystal structure of the complex(D1)₂.Cd(ClO₄)₂. This is a 2:1 (ligand:metal) encapsulating complex. Theperchlorate ions are not shown.

FIG. 13 shows the X-ray crystal structure of the complex(D1)₂.Hg(ClO₄)₂. This is a 2:1 (ligand:metal) encapsulating complex.Additional perchlorate ions belonging to a nearby complex (not shown)also appear.

FIG. 14 shows the X-ray crystal structure of the complex D1.Pb(ClO₄)₂.This is a 1:1 complex (ligand:metal).

FIG. 15 shows the X-ray crystal structure of the complex D1.HClO₄. TheD1 compound is monoprotonated.

FIG. 16 shows the X-ray crystal structure of the free D1 compound withwater and chloroform solvent molecules.

FIG. 17 shows the X-ray crystal structure of the free D1 compound withchloroform solvent molecules.

DETAILED DESCRIPTION

The present disclosure may be understood more readily by reference tothe following detailed description of desired embodiments and theexamples included therein. In the following specification and the claimswhich follow, reference will be made to a number of terms which shall bedefined to have the following meanings.

The singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise.

As used in the specification and in the claims, the term “comprising”may include the embodiments “consisting of” and “consisting essentiallyof.”

Numerical values should be understood to include numerical values whichare the same when reduced to the same number of significant figures andnumerical values which differ from the stated value by less than theexperimental error of conventional measurement technique of the typedescribed in the present application to determine the value.

All ranges disclosed herein are inclusive of the recited endpoint andindependently combinable (for example, the range of “from 2 grams to 10grams” is inclusive of the endpoints, 2 grams and 10 grams, and all theintermediate values).

As used herein, approximating language may be applied to modify anyquantitative representation that may vary without resulting in a changein the basic function to which it is related. Accordingly, a valuemodified by a term or terms, such as “about” and “substantially,” maynot be limited to the precise value specified. The modifier “about”should also be considered as disclosing the range defined by theabsolute values of the two endpoints. For example, the expression “fromabout 2 to about 4” also discloses the range “from 2 to 4.”

Disclosed herein are highly preorganized C-shaped multidentate receptorsfor metal ions. These receptors incorporate the structural properties of8-hydroxyquinoline, and generally possess exposed hydroxyl (—OH) groupsthat can be used for further functionalization, resulting in hexa-,hepta-, octa-, or even higher denticity. These receptors/compounds aregenerally formed from different scaffolds disclosed herein. Whensuitably substituted, the scaffolds for these compounds can be made intomacrocycles, preorganized lariat-ether like receptors, chiral catalysts,building blocks to make molecular springs (when connected in series),metal-organic frameworks, and/or water soluble ligands that can be usedwith suitable metal ions. The additional chelating arms that can beattached to these hydroxyl groups may incorporate a variety ofnitrogen-, oxygen-, or sulfur-containing groups, or other knownfluorophores to facilitate discrimination in metal ion binding abilitiesand therefore metal ion selectivity. The scaffolds can also besubstituted at the aromatic rings to fine-tune the optical properties ofthese molecules and/or for the generation of cyclic structures.

The compounds disclosed herein are highly preorganized (S1, S4) orpartially pre-organized (S2, S3). The phrase highly preorganized is usedto indicate that the compounds have no relevant entropic energy costassociated with metal ion binding. The compounds of the presentdisclosure generally adopt only one conformation. In contrast, othercompounds can adopt numerous conformations and require expenditure ofenergy to adopt the conformation that is suitable for binding a givenmetal ion. The full preorganization of the present compounds leads to acavity of fixed size, which can help discriminate between metal ions ofdifferent ionic radius, and thus provide better selectivity. Lesspreorganized receptors adopt multiple conformations and are thereforeless selective. Generally, the fixed cavity size of the compounds of thepresent disclosure is suitable for metal ions with ionic radius of about1.0 angstroms (ca. 1.0 Å).

The compounds of the present disclosure typically are at leasttetradentate, and can be heptadentate, and can have even higherdenticity. Higher denticity results in a more efficient binding of metalions, as there are more “claws” to grab the ion of interest. They alsopossess exposed hydroxyl groups, which can be used for the attachment ofa variety of ligands that can lead to increased denticity usingsubstitution by simple Sn2 or acylation reactions. In contrast, thedenticity of existing compounds is capped.

Other substitutions can lead to the synthesis of molecular coils (due tothe non-planar structure of the scaffolds), macrocycles, or lariatether-like receptors. The additional chelating ligands that can beintroduced may include a variety of nitrogen-, oxygen-, orsulfur-containing groups, which permit tuning of the binding propertiesof the overall compound by regulating the affinity of metal ions forthese additional chelating ligands.

The present disclosure thus relates to four different scaffold compoundsdenoted (S1), (S2), (S3), and (S4) herein, and to several subgenera andspecies thereof which are generated by appropriate substitution atvarious locations on the scaffold compounds. The scaffold compounds canbe used as molecular compounds, or can be used as monomers in linear,branched, or cyclic polymers.

For purposes of the present disclosure, the term “polymer” refers to anymolecule in which two or more monomers based on a scaffold compound canbe identified. It is recognized that the term “oligomer” is used torefer to molecules that contain a few monomers; however, because thereis no generally recognized threshold in the number of monomers thatdistinguishes between an oligomer and a polymer, the term “polymer” isused herein to encompass both concepts.

Scaffold S1

The first scaffold compound (S1) can be considered as a combination offive rings: two phenyl rings at the ends to which the oxygen atoms areattached, two pyridine rings, and one cyclohexane ring. The firstscaffold compound is based off ofdihydroxy-3,3′-dimethylene-2,2′-biquinoline, and has the followingformula:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂ areindependently selected from hydrogen, halogen, alkyl, substituted alkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, hydroxyl, aldehyde,carboxy, ester, sulfonate, sulfonamide, carboxamide, amino, nitro,nitroso, nitrile, azo, and a water-solubilizing group;wherein one of R₁ to R₅ is —OR′, —SR′, or —NR′₂;one of R₈ to R₁₂ is —OR″, —SR″, or —NR″₂; andwherein R′ and R″ are independently selected from hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, or a chelating ligand comprising at least one linking groupand at least one heteroatom, or together form a linking moiety thatcontains at least one heteroatom, so that the compound is a macrocycliccompound. Exemplary water-solubilizing groups include, but are notlimited to, sugars and polyethers.

The term “alkyl” refers to a radical composed entirely of carbon atomsand hydrogen atoms which is fully saturated. The alkyl radical may belinear, branched, or cyclic. The alkyl radical has the ability to form asingle bond to one or two different non-hydrogen atoms, depending on thecontext. For example, the formulas —CH₂—CH₃ and —CH₂—CH₂— should both beconsidered alkyl. As used herein, an alkyl group has from 1 to about 18carbon atoms.

The term “aryl” refers to an aromatic radical composed entirely ofcarbon atoms, and optionally hydrogen atoms along the perimeter of theradical. The aromatic radical can take any shape. For example, thearomatic radical can be a planar radical such as phenyl or napthyl, orcan be three-dimensional such as fullerene (e.g. C₆₀) or a carbonnanotube. It is noted that these three-dimensional radicals do not haveany hydrogen atoms. When aryl is described in connection with anumerical range of carbon atoms, it should not be construed as includingsubstituted aromatic radicals. For example, the phrase “aryl containingfrom 6 to 10 carbon atoms” should be construed as referring to a phenylgroup (6 carbon atoms) or a naphthyl group (10 carbon atoms) only, andshould not be construed as including a methylphenyl group (7 carbonatoms). The aryl radical has the ability to form a single bond to one ortwo different non-hydrogen atoms, depending on the context. For example,the radicals —C₆H₅ and —C₆H₄— could both be referred to as phenyl andshould both be considered aryl radicals. As used herein, an aryl grouphas from 6 to about 120 carbon atoms, and in narrower embodiments hasfrom 6 to about 10 carbon atoms.

The term “heteroaryl” refers to a cyclic radical composed of carbonatoms, hydrogen atoms, and a heteroatom within a ring of the radical,the cyclic radical being aromatic. The heteroatom may be nitrogen,sulfur, or oxygen. Exemplary heteroaryl groups include thienyl,pyridinyl, furanyl, pyrryl, indolyl, and quinolinyl. When heteroaryl isdescribed in connection with a numerical range of carbon atoms, itshould not be construed as including substituted heteroaromaticradicals. The heteroaryl radical has the ability to form a single bondto one or two different non-hydrogen atoms, depending on the context.For example, the radicals —C₄H₃S and —C₄H₂S— could both be referred toas thienyl, and should both be considered heteroaryl radicals. As usedherein, a heteroaryl group has from 5 to about 18 carbon atoms.

The term “pyridinyl” refers to a radical formed by removing one or twohydrogen atoms from the heterocyclic compound pyridine.

The term “furanyl” refers to a radical formed by removing one or twohydrogen atoms from the heterocyclic compound furan.

The term “pyrryl” refers to a radical formed by removing one or twohydrogen atoms from the heterocyclic compound pyrrole.

The term “thienyl” refers to a radical formed by removing one or twohydrogen atoms from the heterocyclic compound thiophene

The term “indolyl” refers to a radical formed by removing one or twohydrogen atoms from a heterocyclic compound formed by the fusing ofbenzene with pyrrole (e.g. indole or isoindole).

The term “quinolinyl” refers to a radical of the formula by removing oneor two hydrogen atoms from an acene having at least one carbon atomreplaced with a nitrogen atom (e.g. quinoline, isoquinoline,quinoxaline, acridine, etc).

The term “heteroatom” refers to only oxygen, nitrogen, and sulfur.

The term “chelating ligand” refers to a radical that is able to bind toa metal atom to form a coordination complex. A chelating ligand isformed from a combination of at least one linking group and at least oneheteroatom. The chelating ligand may or may not possess one or morechiral centers. The chelating ligand is a linear radical, or in otherwords is linked to the scaffold compound via a bond at one end of theradical. The linking group can be made from any suitable combination ofatoms, such as alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, and amino. Exemplary chelating ligands arefurther described herein.

The term “macrocyclic compound” refers to a cyclic compound thatcontains multiple potential donor atoms that can coordinate to a metalcenter. At least one heteroatom in the linking moiety must be apotential donor atom. The linking moiety can be made from any suitablecombination of atoms, such as alkyl or aryl or multiple heteroatoms.

The term “halogen” refers to fluorine, chlorine, bromine, and iodine.

The term “alkenyl” refers to a radical composed entirely of carbon atomsand hydrogen atoms which contains at least one carbon-carbon double bondthat is not part of an aryl or heteroaryl structure. The alkenyl radicalmay be linear, branched, or cyclic. The alkenyl radical may be bonded toone or two different non-hydrogen atoms, depending on the context.

The term “alkynyl” refers to a radical composed entirely of carbon atomsand hydrogen atoms which contains at least one carbon-carbon triplebond. The alkynyl radical may be bonded to one or two differentnon-hydrogen atoms, depending on the context.

The term “hydroxyl” refers to the —OH radical.

The term “aldehyde” refers to a radical of the formula —CO—R, where R ishydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, and alsorefers to the salt thereof (when R is absent and the oxygen atom has avalence of −1). The term “alkylcarbonyl” is a subset of aldehyderadicals.

The term “carboxy” refers to a radical of the formula —COOR, where R ishydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, and alsorefers to the salt thereof. The carboxy radical bonds through the carbonatom. The term “alkoxycarbonyl” is a subset of carboxy radicals.

The term “alkoxy” refers to an alkyl radical which is attached to anoxygen atom, i.e. —O—C_(n)H_(2n+1).

The term “ester” refers to a radical of the formula —OCOR, where R ishydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, and alsorefers to the salt thereof. The ester radical bonds through an oxygenatom.

The term “sulfonate” refers to a radical of the formula —SO₂—OR, where Ris hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, andalso refers to the salt thereof.

The term “sulfonamide” refers to a radical of the formula —SO₂—NR¹R²,where R¹ and R² are independently hydrogen, alkyl, substituted alkyl,aryl, or substituted aryl.

The term “carboxamide” refers to a radical of the formula —CO₂—NR¹R²,where R¹ and R² are independently hydrogen, alkyl, substituted alkyl,aryl, or substituted aryl.

The term “amino” refers to a radical of the formula —NR¹R², where R¹ andR² are hydrogen, independently alkyl, substituted alkyl, aryl, orsubstituted aryl.

The term “nitro” refers to a radical of the formula —NO₂.

The term “nitroso” refers to a radical of the formula —N═O.

The term “nitrile” refers to a radical of the formula —C≡N.

The term “carbonyl” refers to a radical of the formula —CO—.

The term “azo” refers to a radical containing an —(R¹)_(m)—N═N—(R²)_(n),where m and n are independently 0 or 1, R¹ is alkyl or substitutedalkyl, and R² is hydrogen, alkyl, substituted alkyl, aryl, orsubstituted aryl.

The term “sugar” refers to a radical of the formula —C_(n)H_(2n-1)O_(n),wherein n is between 3 and 30, and contains a number of hydroxyl groupsand at least one carbonyl group. This term should be considered toinclude any number of saccharides covalently bonded together.

The term “polyether” refers to a radical of the formula—(CH₂)_(n)—[O—(CH₂)_(k)]_(m)—OR, wherein R is hydrogen, alkyl,substituted alkyl, aryl, or substituted aryl; wherein n is an integerfrom k, m, and n are independently integers from 1 to 10; and alsorefers to the salt thereof.

The term “substituted” refers to at least one hydrogen atom on the namedradical being substituted with another functional group. An exemplarysubstituted alkyl group is a perhaloalkyl group, wherein one or morehydrogen atoms in an alkyl group are replaced with halogen atoms. Analkyl, alkenyl, or alkynyl group can be substituted with an aryl,substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, hydroxyl,cyano, amino, nitro, nitroso, nitrile, halogen, or azo group. An aryl orheteroaryl group can be substituted with an alkyl, substituted alkyl,alkoxy, hydroxyl, cyano, amino, nitro, nitroso, nitrile, and/or halogengroup. As another example, the radical —COC(OCH₃)(C₆H₅)CF₃ could beconsidered a substituted alkylcarbonyl, where an ethyl radical has beensubstituted with three fluorine atoms on the beta carbon and with amethoxy group and a phenyl group on the alpha carbon. Please note thatthe functional group can itself be substituted.

The compound of Formula (S1) can be asymmetrical or symmetrical. Inparticular embodiments of Formula (S1), the compound is symmetrical. Inspecific embodiments of Formula (S1), one of R₁ to R₅ is —OR′, and oneof R₈ to R₁₂ is —OR″. The —OR′ and —OR″ groups are usually locatedsymmetrically. In particular embodiments, the —OR′ and —OR″ groups arelocated at R₁ and R₁₂.

In more specific embodiments of Formula (S1), R′ and R″ are chelatingligands, and the heteroatom of the chelating ligand is present as acarbonyl group. In other embodiments, the chelating ligand is —CO—R,—(CH₂)_(n)—CO—OR, —(CH₂)_(n)—CO—NR¹R², —(CH₂)_(n)—Z—(CH₂)_(m)—CO—OR,—(CH₂)_(n)—NR³—(CH₂)_(m)—CO—OR, —(CH₂)_(n)—[O—(CH₂)_(k)]_(m)—OR, orsalts thereof; wherein k, m, and n are independently integers from 0 to10; R, R¹, R², and R³ are independently hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;and Z is sulfur or oxygen. Specific examples of such chelating ligandsinclude —CH₂—CO—OCH₃, and —CH₂—CO—O⁻. It is believed that chelatingligands incorporating sulfur atoms may lead to selectivity towardsHg(II) ions. It should be noted that R′ and R″ are usually the same.

In some narrower embodiments of Formula (S1), R₄ and R₉ are the same,and are not hydrogen. For example, in particular embodiments, R₄ and R₉are halogen, aryl, substituted aryl, alkynyl, or substituted alkynyl. Inparticular embodiments, R₂, R₃, R₅, R₆, R₈, R₁₀, and R₁₁ are hydrogen,while R₄ and R₉ are the same and are not hydrogen.

Specific derivatives of the scaffold compound (S1) include those offormulas (D1)-(D7):

wherein R^(a) and R^(b) are independently alkyl, substituted alkyl,aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R′ and R″are independently alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, or a chelating ligand comprising atleast one linking group and at least one heteroatom; X₁ and X₂ areindependently halogen; and Ar₁ and Ar₂ are independently aryl orsubstituted aryl. In some more specific embodiments of (D1), R^(a) andR^(b) are alkyl, and in particular embodiments are —CH₃. In morespecific embodiments of (D5) and (D6), the linkages are connected at theR₄ and R₉ positions, i.e. para to the phenolic oxygen atoms.

As previously noted, macrocyclic compounds of Formula (S1) are alsocontemplated. In these compounds, a linking moiety connects the twooxygen atoms of the —OR′ and the —OR″ groups together. Macrocycliccompounds of Formula (S1) may have the general structure of Formula(S1-M):

wherein R₂-R₁₁ are as defined above, p and q are independently integersfrom 1 to 10; and L is a linking group. The linking group can be madefrom any suitable combination of atoms, including alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, and amino.

Specific examples of exemplary macrocyclic compounds are illustrated inFormulas (M1)-(M7):

wherein p, q, and t are independently integers from 1 to 10; Z is oxygenor sulfur; L′ and L″ are independently O, S, or NR′; R′, R₁₃, and R₁₄are independently hydrogen, alkyl, substituted alkyl, aryl, orsubstituted aryl; and wherein R₄ and R₉ are independently selected fromhydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, hydroxyl, aldehyde, carboxy, ester,sulfonate, sulfonamide, carboxamide, amino, nitro, nitroso, nitrile,azo, and a water-solubilizing group.

Polymers using the compounds of Formula (S1) as a monomer are alsocontemplated. The monomers are linked through the oxygen atoms of thecompound (S1), or through the carbon atoms on the phenyl rings. Thepolymers can be linear, cyclic, or branched. For example, the compound(D1) is used as the monomer in the polymers of Formulas (P1)-(P6)depicted below. For simplicity, the —OR′ and —OR″ groups are illustratedas being located at R₁ and R₁₂, though they can generally be located asdescribed above.

wherein L¹, L², and L³ are independently linking groups; R′ and R″ areindependently alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, or a chelating ligand comprising atleast one linking group and at least one heteroatom; and n is the degreeof polymerization, and is from 0 to about 100. In (P2), w is the degreeof polymerization, and is from 2 to about 100. Again, the linking groupscan be made from any suitable combination of atoms, including alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,and amino. For example, the linking groups could be alkyl. It is notedthat the polymers can be homopolymers or copolymers (i.e. two or moredifferent monomers). It is noted that (P3) is a cyclic polymer wheren=2, and that (P4)-(P6) are cyclic polymers.

For clarity, it is noted that in (P4)-(P6), L² is within the repeatingunit, while L³ is outside the repeating unit. It should be noted that in(P5), the linkages L¹, L², and L³ can be through any of the carbon atomson the phenyl ring, (i.e. ortho-, meta-, or para-) depending on theidentity of the linkage. It should be noted that in (P4)-(P6), dependingon the location of the linkages and the number of repeating units, thevarious portions of the cyclic polymer can rotate so that the R′ and R″groups are directed to the interior or the exterior of the cyclicpolymer, whichever is more stable.

Derivatives D2 and D3 can be used as an MRI contrast agent when bound tosuitable metal ions such as Gd(III). These derivatives can permit thechelation of two water molecules to Gd(III), which is twice as many asin current commercial products. This is expected to lead to eitherincreased resolution or to a reduced dose of the contrast agent.

The derivative D1 exhibits an intrinsic blue fluorescence in the solidstate and in solution (i.e. acetonitrile). This fluorescence can bered-shifted to any portion of the visible spectrum by selection of anappropriate metal ion or acid. Derivative D1 can therefore serve as aratiometric multicolor fluorescence generator and operate as a“universal” sensor that permits identification of the presence of agiven metal ion based on the color of the fluorescence. D1 can alsoserve as an on/off switch because its intrinsic blue fluorescence canalso be quenched if certain metal ions are present. That D1 binds themetal ion or acid has been confirmed by solution studies (fluorescence,¹H NMR spectroscopy) and X-ray crystallography.

These properties of D1 are shown in FIGS. 1-7. FIG. 1 shows D1 insolution by itself, and with various metal ions added and the resultingcolor listed below. With no metal, the D1 solution was blue. With Mg²⁺,the solution was a blue-green color. With Sr²⁺, the solution was agreen-blue color. With Ca²⁺, the solution was a green color. With Cd²⁺,the solution was an olive green color. With Zn²⁺, the solution was ayellow-orange color. With H⁺, the solution was a red color.

FIG. 2 shows D1 in the solid state (i.e. powder), and with various metalions added and the resulting color listed below. With no metal, the D1powder was blue. With Ca²⁺, the powder was a blue-green color. WithSr²⁺, the powder was a green color. With Cd²⁺, the powder was ayellow-green color. With Zn²⁺, the powder was a yellow color. With Ba²⁺,the powder was a dark yellow color. With K⁺, the powder was an orangecolor. With H⁺, the powder was a red color. With Ni²⁺, the powder wasblack (i.e. fluorescence was quenched).

Comparing FIG. 1 and FIG. 2, there is a clear difference in color when ametal ion is present. It is noted that the color for a given metal ionmay change between the solution and the solid state. However, each coloris still unique for a given metal ion. Note that nickel (Ni²⁺) quenchedthe intrinsic blue color of D1.

FIG. 3 shows the normalized emission spectra for six complexes,indicating that the different metal ions can be distinguished from eachother reasonably well.

FIG. 4 shows solutions of D1 with various metal ions in solution underboth ordinary light and UV light (365 nm). Under UV light, the D1solution alone is blue. With Ca(II), the solution is green. With Zn(II),the solution is yellow-orange. With Al(III), the solution is red. WithPb(II), the solution is black, i.e. the blue color that would other bevisible has been quenched.

FIG. 5 is a set of pictures showing fluorescence of D1 in the solidstate, under ordinary light (top row) and under UV light (365 nm)(bottom row). In column A, the free ligand sample (i.e. no metal ions)is blue. In column B with Ca(II), the powder is green. In column C withZn(II), the powder is yellow. In column D with Al(III), the powder isred. In column E with Pb(II), the powder is non-fluorescent.

FIG. 6 is a set of pictures showing fluorescence of D1 in the solidstate, under ordinary light (top row) and under UV light (365 nm)(bottom row). In the first column with La(III), the powder fluorescesred. In the second column with Co(II), the powder is non-fluorescent. Inthe third column with Ni(II), the powder is non-fluorescent. In thefourth column with Cu(II), the powder is non-fluorescent.

FIG. 7 is a set of pictures showing fluorescence of D1 in the solidstate, under ordinary light (top row) and under UV light (365 nm)(bottom row). In the first column with silver nitrate (AgNO₃), thepowder is non-fluorescent. In the second column with Hg(II), the powderbarely fluoresces. In the third column with Pb(II), the powder isnon-fluorescent. In the fourth column, the free compound D7 is shown,and is non-fluorescent.

Scaffold S2

The second scaffold compound (S2) is a combination of twohydroxyquinolines, i.e. having two phenyl rings and two pyridine rings.The second scaffold compound is based off of adimethoxy-2,2′-biquinoline, and has the following formula:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂ areindependently selected from hydrogen, halogen, alkyl, substituted alkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, hydroxyl, aldehyde,carboxy, ester, sulfonate, sulfonamide, carboxamide, amino, nitro,nitroso, nitrile, azo, and a water-solubilizing group, and wherein R₆and R₇ may be joined together via an alkyl or substituted alkyl linkageto form a cyclic ring;wherein one of R₁ to R₅ is —OR′, —SR′, or —NR′₂;one of R₈ to R₁₂ is —OR″, —SR″, or —NR″₂; andwherein R′ and R″ are independently alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, or a chelatingligand comprising at least one linking group and at least oneheteroatom, or together form a linking moiety that contains at least oneheteroatom, so that the compound is a macrocyclic compound.

When R₆ and R₇ are not joined together, then unlike the compound ofFormula (S1), the two nitrogen atoms of the pyridine rings are not fixedin position relative to each other. Thus, the cavity size of (S2) canchange more readily compared to (S1). However, if R₆ and R₇ are joinedtogether, then Formula (S2) can overlap with Formula (S1) when R₆ and R₇are —CH₂—CH₂—.

The compound of Formula (S2) can be asymmetrical or symmetrical. Inparticular embodiments of Formula (S2), the compound is symmetrical. Inspecific embodiments of Formula (S2), one of R₁ to R₅ is —OR′, and oneof R₈ to R₁₂ is —OR″. The —OR′ and —OR″ groups are usually locatedsymmetrically. In particular embodiments, the —OR′ and —OR″ groups arelocated at R₁ and R₁₂.

In more specific embodiments of Formula (S2), R′ and R″ are chelatingligands, and the heteroatom of the chelating ligand is present as acarbonyl group. In other embodiments, the chelating ligand is —CO—R,—(CH₂)_(n)—CO—OR, —(CH₂)_(n)—CO—NR¹R², —(CH₂)_(n)—Z—(CH₂)_(m)—CO—OR,—(CH₂)_(n)—NR³—(CH₂)_(m)—CO—OR, —(CH₂)_(n)—[O—(CH₂)_(k)]_(m)—OR, orsalts thereof; wherein k, m, and n are independently integers from 0 to10; R, R¹, R², and R³ are independently hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;and Z is sulfur or oxygen. Specific examples of such chelating ligandsinclude —CH₂—CO—OCH₃ and —CH₂—CO—O⁻. In other specific embodiments, R′and R″ are alkyl or substituted alkyl. It is believed that chelatingligands incorporating sulfur atoms may lead to selectivity towardsHg(II) ions. It should be noted that R′ and R″ are usually the same. Itshould also be noted that when R₁ and R₁₂ are hydroxyl, the resultingcompound is not luminescent.

In other embodiments of Formula (S2), R₄ and R₉ are the same, and arenot hydrogen. For example, in particular embodiments, R₄ and R₉ arehalogen, aryl, substituted aryl, alkynyl, or substituted alkynyl. Inparticular embodiments, R₂, R₃, R₅, R₆, R₇, R₈, R₁₀, and R₁₁ arehydrogen, while R₄ and R₉ are the same and are not hydrogen. In yetother embodiments, all of R₂-R₁₁ are hydrogen.

Specific derivatives of the scaffold compound (S2) include those offormulas (B1)-(B3):

wherein R¹ and R² are independently alkyl or substituted alkyl; R′ andR″ are independently alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, or a chelating ligand comprising atleast one linking group and at least one heteroatom; and X₁ and X₂ areindependently halogen; and n is an integer from 1 to 10 in (B3). In aspecific embodiment of B1, R¹ and R² are —CH₃.

Macrocyclic compounds of Formula (S2) and polymers using the compoundsof Formula (S2) as a monomer are also contemplated. In the macrocycliccompounds, a linking moiety connects the two oxygen atoms of the —OR′and the —OR″ groups together. Macrocyclic compounds of Formula (S2) havethe general structure of Formula (S2-M):

wherein R₂-R₁₁ are as defined above, p and q are independently integersfrom 1 to 10; and L is a linking group. Again, the linking group can bemade from any suitable combination of atoms, including alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,and amino. Those linking groups illustrated in Formulas (M1)-(M7) canalso apply here.

In the polymers, the monomers are linked through the oxygen atoms, orthrough the carbon atoms on the phenyl rings. Specific examples followthe general formula shown above with respect to Formula (S1), and areillustrated below as Formulas (P7)-(P12). Again, for simplicity, the—OR′ and —OR″ groups are illustrated as being located at R₁ and R₁₂,though they can generally be located as described above.

wherein L¹, L², and L³ are independently linking groups; R′ and R″ areindependently alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, or a chelating ligand comprising atleast one linking group and at least one heteroatom; and n is the degreeof polymerization, and is from 0 to about 100. In (P8), w is the degreeof polymerization, and is from 2 to about 100. Again, the linking groupscan be made from any suitable combination of atoms, including alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, and amino. For example, the linking groups could be alkyl.It is noted that the polymers can be homopolymers or copolymers (i.e.two or more different monomers).

For clarity, it is noted that in (P10)-(P12), L² is within the repeatingunit, while L³ is outside the repeating unit. It should be noted that in(P11) and (P12), the linkages L¹, L², and L³ can be through any of thecarbon atoms on the phenyl ring, (i.e. ortho-, meta-, or para-)depending on the identity of the linkage. It should be noted that in(P10)-(P12), depending on the location of the linkages and the number ofrepeating units, the various portions of the cyclic polymer can rotateso that the R′ and R″ groups are directed to the interior or theexterior of the cyclic polymer, whichever is more stable.

Manufacture of Scaffolds S1 and S2

The compounds of Formula (S1) and Formula (S2) can be made using aFriedlander condensation involving a diketone and at least oneo-aminobenzaldehyde (depending on whether the compound is symmetric orasymmetric). When making a compound of Formula (S1), the diketone is a1,2-cyclohexanedione. When making a compound of Formula (S2), thediketone is a 2,3-butadione.

Synthesis Scheme 1 illustrates a two-step reaction to produce a compoundof Formula (S1) using two aminobenzaldehydes (AA1) and (AA2) and adiketone (S1a). Synthesis Scheme 2 illustrates a two-step reaction toproduce a compound of Formula (S2) using two aminobenzaldehydes (AA1)and (AA2) and a diketone (S2a). For simplicity, the —OR′ and —OR″ groupsare illustrated below at the R₁ and R₁₂ positions. Of course, therelative locations of the amino group, the —OR′/—OR″ group, and thealdehyde group will change depending on the location of the —OR′/—OR″group.

The reaction typically occurs in the presence of a base and an alcohol,e.g. potassium hydroxide (KOH) and ethanol (EtOH). Once theaminobenzaldehyde is consumed, trifluoroacetic acid is added todehydrate and precipitate the compound out of solution. The use of thisdehydrating reagent is important in the synthesis of the compound.

It should be noted that the aminobenzaldehydes (AA1) and (AA2) can bethe same. In this event, the reactions would be one-step reactions usingtwo moles of the aminobenzaldehyde per mole of diketone.

The substituents R^(a) and R^(b) can be the final desired ligands, orcan be intermediate ligands that are substituted to obtain the finaldesired ligands R′ and R″, whether to form the compounds, or to obtainmacrocyclic compounds or linkers to obtain polymers. The compoundcontaining R^(a) and R^(b) can be reduced with hydrobromic acid toobtain —OH groups, and then be reacted with reactants of the formulaL^(a)-R′ and L^(b)-R″, wherein L^(a) and L^(b) are leaving groups knownin the art, to obtain the final desired ligands.

Scaffold S3

The third scaffold compound (S3) is a combination of two quinolines(each having a phenyl ring and a pyridine ring) and one pyridine ringbridging the two quinoline rings. The third scaffold compound has thefollowing formula:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, andR₁₅ are independently selected from hydrogen, halogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,hydroxyl, aldehyde, carboxy, ester, sulfonate, sulfonamide, carboxamide,amino, nitro, nitroso, nitrile, azo, and a water-solubilizing group;wherein one of R₁ to R₅ is —OR′, —SR′, or —NR′″₂;one of R₁₁ to R₁₅ is —OR″, —SR″, or —NR″″₂;wherein R′ and R″ are independently a chelating ligand comprising atleast one linking group and at least one heteroatom, or together form alinking moiety that contains at least one heteroatom, so that thecompound is a macrocyclic compound; andwherein R′″ and R″″ are independently hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aldehyde,carboxy, ester, or a chelating ligand comprising at least one linkinggroup and at least one heteroatom, or together form a linking moietythat contains at least one heteroatom, so that the compound is amacrocyclic compound.

Again, it should be noted that the nitrogen atoms of the two quinolinerings can move relative to the nitrogen atom of the central pyridinering. Thus, the cavity size can vary.

The compound of Formula (S3) can be asymmetrical or symmetrical. Inparticular embodiments of Formula (S3), the compound is symmetrical. Inspecific embodiments of Formula (S3), one of R₁ to R₅ is —OR′, and oneof R₁₁ to R₁₅ is —OR″. The —OR′ and —OR″ groups are usually locatedsymmetrically. In particular embodiments, the —OR′ and —OR″ groups arelocated at R₁ and R₁₅.

In more specific embodiments of Formula (S3), R′ and R″ are chelatingligands, and the heteroatom of the chelating ligand is present as acarbonyl group. In other embodiments, the chelating ligand is —CO—R,—(CH₂)_(n)—CO—OR, —(CH₂)_(n)—CO—NR¹R², —(CH₂)_(n)—Z—(CH₂)_(m)—CO—OR,—(CH₂)_(n)—NR³—(CH₂)_(m)—CO—OR, —(CH₂)_(n)—[O—(CH₂)_(k)]_(m)—OR, orsalts thereof; wherein k, m, and n are independently integers from 0 to10; R, R¹, R², and R³ are independently hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;and Z is sulfur or oxygen. Specific examples of such chelating ligandsinclude —CH₂—CO—OCH₃, —CO—CH₃, and —CO—C(CF₃)(OCH₃)(C₆H₅). It isbelieved that chelating ligands incorporating sulfur atoms may lead toselectivity towards Hg(II) ions. It should be noted that R′ and R″ areusually the same. In particular embodiments, all of R₂-R₁₄ are hydrogen.

Also falling within the scope of formula (S3) are symmetric compounds offormula (S3-I):

wherein p is an integer from 0 to 4; R is hydrogen, hydroxyl or a saltthereof, alkyl, substituted alkyl, alkoxy, or substituted alkoxy; and R₄and R₁₂ are independently selected from hydrogen, halogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,hydroxyl, aldehyde, carboxy, ester, sulfonate, sulfonamide, carboxamide,amino, nitro, nitroso, nitrile, azo, and a water-solubilizing group. Inparticular embodiments of (S3-I), R₄ and R₁₂ are the same, and are nothydrogen.

Specific derivatives of the scaffold compound (S3) include those offormulas (L1), (L2), and (L3):

Compound (L1) is also known as2,6-bis[8-(methoxycarbonylmethoxy)quinolin-2-yl]pyridine. Compound (L2)is also known as 2,6-bis[8-(acetoxy)quinolin-2-yl]pyridine. Compound(L3) is also known as2,6-bis[8-((2R)-2-trifluoromethyl-2-methoxy-2-phenylacetoxy)quinolin-2-yl]pyridine.These are heptadentate compounds.

Macrocyclic compounds of Formula (S3) and polymers using the compoundsof Formula (S3) as a monomer are also contemplated. In the macrocycliccompounds, a linking moiety connects the two oxygen atoms of the —OR′and the —OR″ groups together. Macrocyclic compounds of Formula (S3) mayhave the general structure of Formula (S3-M):

wherein R₂-R₁₄ are as defined above, p and q are independently integersfrom 1 to 10; and L is a linking group. Again, the linking group can bemade from any suitable combination of atoms, including alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,and amino. Those linking groups illustrated in Formulas (M1)-(M7) canalso apply here.

In the polymers, the monomers are linked through the phenolic oxygenatoms, or through the carbon atoms on the phenolic rings. Specificexamples of polymers are illustrated below as Formulas (P13)-(P20). Forsimplicity, the —OR′ and —OR″ groups are illustrated as being located atR₁ and R₁₅, though they can generally be located as described above.

wherein L¹, L², and L³ are independently linking groups; R′ and R″ areindependently a chelating ligand comprising at least one linking groupand at least one heteroatom; and n is the degree of polymerization, andis from 0 to about 100. In (P13), w is the degree of polymerization, andis from 2 to about 100. Again, the linking groups can be made from anysuitable combination of atoms, including alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, and amino. Forexample, the linking groups could be alkyl. It is noted that thepolymers can be homopolymers or copolymers (i.e. two or more differentmonomers).

For clarity, it is noted that in (P15)-(P20), L² is within the repeatingunit, while L³ is outside the repeating unit. It should be noted that in(P15)-(P20), the linkages L¹, L², and L³ can be through any of thecarbon atoms on the given ring, depending on the identity of thelinkage. In particular embodiments of (P16), the linkage is through thecarbon atom that is meta- (either one or both) or para- to the nitrogenatom. It should be noted that in (P15)-(P20) the various portions of thecyclic polymer can rotate so that the R′ and R″ groups are directed tothe interior or the exterior of the cyclic polymer, whichever is morestable.

Manufacture of Scaffold S3

The manufacture of the base scaffold compound (S3), where all of the Rgroups, R′, and R″ are all hydrogen, is known in the chemicalliterature. This base compound can be reacted with reactants of theformula L^(a)-R′ and L^(b)-R″, wherein L^(a) and L^(b) are leavinggroups known in the art, to obtain the final desired ligands.

Scaffold S4

The fourth scaffold compound (S4) is a combination of two quinolines(each having a phenyl ring and a pyridine ring) attached at the oppositeends of a tetrahydroacridine. The resulting compound has a centralpyridine ring, two cyclohexane rings, two flanking pyridine rings, andtwo terminal phenyl rings. The fourth scaffold compound has thefollowing formula:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄,R₁₅, R₁₆, R₁₇, R₁₈, and R₁₉ are independently selected from hydrogen,halogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, hydroxyl, aldehyde, carboxy, ester, sulfonate,sulfonamide, carboxamide, amino, nitro, nitroso, nitrile, azo, and awater-solubilizing group;wherein one of R₁ to R₅ is —OR′, —SR′, or —NR′″₂;one of R₁₅ to R₁₉ is —OR″, —SR″, or —NR″″₂;wherein R′ and R″ are independently a chelating ligand comprising atleast one linking group and at least one heteroatom, or together form alinking moiety that contains at least one heteroatom, so that thecompound is a macrocyclic compound; andwherein R′″ and R″″ are independently hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aldehyde,carboxy, ester, or a chelating ligand comprising at least one linkinggroup and at least one heteroatom, or together form a linking moietythat contains at least one heteroatom, so that the compound is amacrocyclic compound.

It should be noted that the three nitrogen atoms of the pyridine ringsare fixed in position relative to each other. This reduces the abilityof the compound to vary the cavity size.

The compound of Formula (S4) can be asymmetrical or symmetrical. Inparticular embodiments of Formula (S4), the compound is symmetrical. Inspecific embodiments of Formula (S4), one of R₁ to R₅ is —OR′, and oneof R₁₅ to R₁₉ is —OR″. The —OR′ and —OR″ groups are usually locatedsymmetrically. In particular embodiments, the —OR′ and —OR″ groups arelocated at R₁ and R₁₉.

In more specific embodiments of Formula (S4), R′ and R″ are chelatingligands, and the heteroatom of the chelating ligand is present as acarbonyl group. In other embodiments, the chelating ligand is analkylcarbonyl, —CO—R, —(CH₂)_(n)—CO—OR, —(CH₂)_(n)—CO—NR¹R²,—(CH₂)_(n)—Z—(CH₂)_(m)—CO—OR, —(CH₂)_(n)—NR³—(CH₂)_(m)—CO—OR,—(CH₂)_(n)—[O—(CH₂)_(k)]_(m)—OR, or salts thereof; wherein k, m, and nare independently integers from 0 to 10; R, R¹, R², and R³ areindependently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, or substituted heteroaryl; and Z is sulfur or oxygen.Specific examples of such chelating ligands include —CH₂—CO—OCH₃ and—CO—CH₃. It is believed that chelating ligands incorporating sulfuratoms may lead to selectivity towards Hg(II) ions. It should be notedthat R′ and R″ are usually the same.

In particular embodiments, all of R₂-R₁₈ are hydrogen. In some otherembodiments, R₁₀ is alkyl, and R₂-R₉ and R₁₁-R₁₈ are hydrogen.

Also falling within the scope of formula (S4) are symmetric compounds offormula (S4-I):

wherein p is an integer from 0 to 4; R is hydrogen, hydroxyl or a saltthereof, alkyl, substituted alkyl, alkoxy, or substituted alkoxy; R₁₀ isalkyl; and R₄ and R₁₆ are independently selected from hydrogen, halogen,alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, hydroxyl, aldehyde, carboxy, ester, sulfonate,sulfonamide, carboxamide, amino, nitro, nitroso, nitrile, azo, and awater-solubilizing group.

One specific derivative of the scaffold compound (S4) is that of formula(L4):

Compound (L4) is also known as8-butyl-1,15-bis(methoxycarbonylmethoxy)-diquinolino[2,3-c:3′,2′-h]-6,7,9,10-tetrahydroacridine.This is a heptadentate compound.

Macrocyclic compounds of Formula (S4) and polymers using the compoundsof Formula (S4) as a monomer are also contemplated. In the macrocycliccompounds, a linking moiety connects the two oxygen atoms of the —OR′and the —OR″ groups together. Macrocyclic compounds of Formula (S4) mayhave the general structure of Formula (S4-M):

wherein R₂-R₁₈ are as defined above, p and q are independently integersfrom 1 to 10; and L is a linking group. Again, the linking group can bemade from any suitable combination of atoms, including alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,and amino. Those linking groups illustrated in Formulas (M1)-(M7) canalso apply here.

In the polymers, the monomers are linked through the oxygen atoms, orthrough the carbon atoms on the phenyl rings. Specific examples ofpolymers are illustrated below as Formulas (P21)-(P26). For simplicity,the —OR′ and —OR″ groups are illustrated as being located at R₁ and R₁₉,though they can generally be located as described above.

wherein L¹, L², and L³ are independently linking groups; each R₉ isindependently hydrogen or alkyl; R′ and R″ are independently a chelatingligand comprising at least one linking group and at least oneheteroatom; and n is the degree of polymerization, and is from 0 toabout 100. In (P21), w is the degree of polymerization, and is from 2 toabout 100. Again, the linking groups can be made from any suitablecombination of atoms, including alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, and amino. Forexample, the linking groups could be alkyl. It is noted that thepolymers can be homopolymers or copolymers (i.e. two or more differentmonomers).

For clarity, it is noted that in (P23)-(P26), L² is within the repeatingunit, while L³ is outside the repeating unit. It should be noted that in(P23), (P25), and (P26), the linkages L¹, L², and L³ can be through anyof the carbon atoms on the given ring, depending on the identity of thelinkage. It should be noted that in (P23)-(P26), depending on thelocation of the linkages and the number of repeating units, the variousportions of the cyclic polymer can rotate so that the R′ and R″ groupsare directed to the interior or the exterior of the cyclic polymer,whichever is more stable.

FIG. 8 is a set of pictures showing the fluorescent properties ofcompound L4 in two different solvents (water and chloroform) underordinary light and under UV light (365 nm). Vial #1 contains only L4,Vial #2 contains sodium chloride, Vial #3 contains calcium chloride, andVial #4 contains hydrochloric acid. The two layers in each vial weremixed, then allowed to separate and observed. In Vial #1, L4 is presentin the chloroform layer. There is no reaction to sodium in Vial #2. InVial #3, L4 exhibits an intense blue fluorescent response to Ca²⁺. Inaddition, the complex in Vial #3 migrated to the water layer. It isbelieved that this migration will only occur with a metal ion of theproper size and sufficiently high ionic charge. Vial #4 exhibited agreen fluorescence. Interference from acid is, therefore, not expectedto cause false positive results.

Manufacture of Scaffold S4

The compounds of Formula (S4) can be made using a Friedlandercondensation involving a 1,2,3,6,7,8-hexahydroacridine-4,5-dione and atleast one o-aminobenzaldehyde (depending on whether the compound issymmetric or asymmetric). Synthesis Scheme 3 illustrates a two-stepreaction to produce a compound of Formula (S4) using twoaminobenzaldehydes (AA1) and (AA3) and a hexahydroacridine-4,5-dione(S4a). Again, the aminobenzaldehydes (AA1) and (AA3) could be the same,in which case the reaction would be a one-step reaction using two molesof the aminobenzaldehyde per mole of hexahydroacridine-4,5-dione. Forsimplicity, the —OR′ and —OR″ groups are illustrated below at the R₁ andR₁₉ positions.

The reaction typically occurs in the presence of a base and an alcohol,e.g. potassium hydroxide (KOH) and ethanol (EtOH). Once theaminobenzaldehyde is consumed, trifluoroacetic acid is added toprecipitate the compound out of solution. The reaction also works whencarried out in toluene using methanol and potassium hydroxide, but afully aromatized product (i.e. the cyclohexane rings become aromatic) isgenerated as an impurity. The use of this dehydrating reagent isimportant in the synthesis of the compound.

The substituents R^(a) and R^(b) can be the final desired ligands, orcan be intermediate ligands that are substituted to obtain the finaldesired ligands R′ and R″, whether to form the compounds, or to obtainmacrocyclic compounds or linkers to obtain polymers. The compoundcontaining R^(a) and R^(b) can be reduced with hydrobromic acid toobtain —OH groups, and then be reacted with reactants of the formulaL^(a)-R′ and L^(b)-R″, wherein L^(a) and L^(b) are leaving groups knownin the art, to obtain the final desired ligands.

Referring again to all compounds of the present disclosure, thesecompounds luminesce ratiometrically, i.e. they emit light at onewavelength (i.e. color) in the absence of metal ions and at a differentwavelength/color in the presence of certain metal ions, the differentwavelength depending on the identity of the metal ion. In a compoundthat luminesces ratiometrically, the addition of a metal ion results ina simultaneous decrease in the size of the original fluorescent band ofthe free compound and the appearance of a new band at a differentwavelength. The size of the new luminescent band increases withincreasing concentration of the metal ion at the expense of the originalband, which eventually disappears. This type of behavior provides aninternal reference point against which to measure optical changes, whichis desirable. In contrast, other molecules typically act only as on/offsensors—their luminescence is either triggered or quenched when metalions are present. It is noted that with certain other metal ions, anon-off behavior is observed with the compounds of the presentdisclosure. Complexes with lanthanides such as Eu(III) may be used tosensitize the luminescence of the metal ion.

Appropriate substitutions can also lead to increased water solubilityfor the present compounds, which is useful in practical applications. Nostructural changes to the scaffolds are needed to change the solubilityof these molecules.

The incorporation of chiral groups may lead to chiral catalysts forasymmetric synthesis. It is also contemplated that the opticalproperties and luminescent quantum yield of the compounds can also betuned by substitution on the phenolic rings of the scaffolds.

The compounds of the present disclosure can be immobilized on polymersurfaces for final applications without any modification of thescaffold, as linkers can be attached through the hydroxy groups or anyof the rings. Immobilization is a useful feature, and typically requiresmajor modifications in the synthetic protocol of conventional receptors.Some of the scaffolds of the present disclosure already have a protocolfor permitting immobilization, which facilitates final applications.

The following examples are provided to illustrate various aspects of thecompounds of the present disclosure. The examples are merelyillustrative and are not intended to limit the disclosure to thematerials, conditions, or process parameters set forth therein.

EXAMPLES General

NMR spectra was acquired using Bruker DPX-250, Bruker Avance DMX-600, orBruker Avance DRX-800 spectrometers. Solvents used were CDCl₃ with 0.05%TMS, DMSO-d₆, or CF₃COOD. All chemical shifts (δ) were reported in ppmunits relative to trimethylsilane (TMS) internal reference (δ_(TMS)=0,¹H), CDCl₃ (δ 77.23, ¹³C), DMSO-d₆ (δ 2.54, ¹H; 40.45, ¹³C), or TFA (δ11.5, ¹H; 162.4, ¹³C). The assignment of carbon atoms was done by meansof an attached proton test (APT) experiment. Melting points weremeasured in open glass capillary tubes on a Mel-Temp apparatus and areuncorrected. Infrared spectra (IR) were obtained on a Spectrum RXIPerkin Elmer FT-IR spectrometer and the frequencies reported inwavenumbers (cm⁻¹). High resolution MS was performed using a sodiumiodide matrix.

Example 1

8,8′-Dimethoxy-3,3′-dimethylene-2,2′-biquinoline (D1) was preparedaccording to the following scheme:

To a 50 mL round-bottomed flask equipped with a condenser and nitrogeninlet, all flame-dried, was added a stir bar, powdered potassiumhydroxide (0.12 grams, 2.1 mmol), diketone 2 (0.74 grams, 6.6 mmol), andaminoaldehyde 1 (1.97 grams, 13 mmol) followed by 25 mL of absoluteethanol. The mixture was stirred under nitrogen to give a yellowsolution which was then kept at reflux for one day. The resulting redsolution was concentrated in vacuo, dissolved in 25 mL of warm TFA, and25 mL of absolute ethanol was added to crystallize the product. Aftercooling in an ice-water bath the product was collected by vacuumfiltration and washed with 25 mL of ether. The red powder that wascollected was dried under vacuum for one day to give 2.17 grams of a TFAsalt of compound D1. ¹H NMR (800 MHz, DMSO-d₆) δ 8.34 (s, 2H, H4), 7.57(t, J=7.2 Hz, J′=8.0 Hz, 2H, H6), 7.53 (d, J=8.0 Hz, 2H, H5), 7.19 (d,J=7.2 Hz, 2H, H7), 3.97 (s, 6H, 2×OCH₃), 3.19 (s, 4H, 2×CH₂).

The red powder was dissolved in 250 mL of chloroform and washed with0.03M aqueous tris(hydroxymethyl)aminomethane (2×45 mL, 1×20 mL) andbrine (50 mL). After drying the organic layer over magnesium sulfate andafter drying agent and solvent removal (rotavap), and overnight dryingunder reduced pressure, 1.97 grams (87%) of neutral compound D1 wascollected. Crystals of D1 were obtained by recrystallization from ethylacetate and hexane and after storing the solution near 2° C. for 2 days.Compound D1 crystallized as brown prismatic crystals, mp. 209.4-209.8°C. after dehydration of solvent molecules at 108.8-114.0° C. ¹H NMR (600MHz, CDCl₃) δ 3.23 (s, 4H, CH₂), 4.13 (s, 6H, OCH₃), 7.00 (d, J=7.7 Hz,2H, H3), 7.34 (d, J=8.1 Hz, 2H, H5), 7.46 (t, J=7.7 Hz, 2H, H4), 8.00(s, 2H, H6). ¹³C NMR (150 MHz, CDCl₃) δ 156.5 (C), 151.6 (C), 140.5 (C),134.6 (CH), 133.5 (C), 129.7 (C), 127.8 (CH), 118.9 (CH), 107.3 (CH),77.36 (CHCl₃), 56.0 (OCH₃), 28.9 (ArCH₂). IR (KBr) 3435.8 (OH, s),2942.3 (s), 2840.1 (s), 1629.8 (s), 1554.8 (s), 1490.6 (s), 1466.4 (s),1381.8 (s), 1353.1 (s), 1266.4 (s), 1173.6 (s), 1154.1 (s), 1092.2 (s),1024.0 (s), 916.1 (m), 765.0 (s), 738.6 (s), 714.6 (s). HRMS M+Na⁺(abundance/ppm); calculated for [C₂₂H₁₈N₂NaO₂]⁺: 365.1266; measured:365.1255 (3.0).

Example 2

8,8′-Bis(methoxycarbonylmethoxy)-3,3′-dimethylene-2,2′-biquinoline (D2)was prepared using two different methods, both of which proceededaccording to the following scheme:

First, 8,8′-dihydroxy-3,3′-dimethylene-2,2′-biquinoline (D7) wasprepared by the reduction of compound D1. A solution of D1 (0.40 grams,1.2 mmol) in 25 mL of 48% aqueous hydrobromic acid was kept in refluxfor 28.5 hours. The resulting mixture was then allowed to cool down toroom temperature overnight and the precipitate collected by vacuumfiltration. After washing it with 5 mL of water, it was dried undervacuum overnight to give 0.32 grams of a bright orange-red powder. ¹HNMR (800 MHz, DMSO-d₆) δ 11.26 (br s, 2H, OH), 8.72 (s, 2H, H5), 7.69(t, J=7.7 Hz, 2h, H3), 7.59 (d, J=7.9 Hz, 2H, H4), 7.35 (d, J=7.4 Hz,2H, H2, H2), 3.39 (s, 4H, CH₂). This sample was dissolved in 55 mL ofmethanol and 190 mL of chloroform and washed with 0.07 M aqueoustris(hydroxymethyl)aminomethane (2×75 mL), dried over magnesium sulfate,filtered, the solvent removed using a rotavap, and the residue driedunder vacuum overnight. This afforded 0.26 grams (71%) of product D7 asa yellow solid. The compound can be recrystallized from a small volumeof chloroform. This gives the product as shiny greenish-yellow needles,mp. 294-297° C. ¹H NMR (600 MHz, CDCl₃) δ 3.28 (s, 4H, CH₂), 7.14 (dd,J=8.1 Hz, J′=0.8 Hz, 2H, H3), 7.30 (d, J=8.1 Hz, 2H, H5), 7.45 (t, J=7.8Hz, 2H, H4), 8.06 (s, 2H, H6). ¹³C NMR (150 MHz, CDCl₃) δ 153.7 (C),150.1 (C), 138.5 (C), 135.3 (CH), 133.4 (C), 129.3 (C), 129.1 (CH),117.5 (CH), 110.9 (CH), 77.36 (CHCl₃), 28.8 (ArCH₂). IR (KBr) 3448.3(s), 3307.5 (s), 1607.2 (m), 1561.1 (m), 1494.1 (s), 1466.0 (s), 1333.4(s), 1313.5 (s), 1211.2 (s), 1151.0 (s), 759.6 (s), 538.5 (m). HRMS,M+Na⁺ (abundance/ppm); calculated for [C₂₀D7₄N₂NaO₂]⁺: 337.0953;measured: 337.0948 (1.5).

From D7, two methods were used to obtain D2.

Method 1.

Crude scaffold D7 (0.15 grams, 0.48 mmol), cesium carbonate (0.16 grams,0.48 mmol), and methyl chloroacetate (0.11 grams, 1.0 mmol) were stirredunder nitrogen at room temperature in 25 mL of anhydrous DMF for 2 days.During this period, additional drops of methyl chloroacetate were addeduntil scaffold D7 was no longer detected by TLC (silica gel, MeCN:NH₄OH,9:1, v/v). The mixture was then vacuum filtered, the precipitate washedwith a few milliliters of a solution of hexane/chloroform (9:1), and thefiltrate concentrated in vacuo. This gave crude compound D2 as a blacksolid (quantitative yield). ¹H NMR (600 MHz, TFA-d) δ 9.11 (s, 2H, H5),7.97 (t, J=8.2 Hz, J′=8.0 Hz, 2H, H3), 7.92 (d, J=8.3 Hz, 2H, H4), 7.57(d, J=7.7 Hz, 2H, H2), 5.26 (s, 4H, CH₂), 3.93 (s, 6H, OCH₃), 3.62 (s,4H, ArCH₂). HRMS, M+Na⁺ (abundance/ppm); calculated for [C₂₆H₂₂N₂NaO₆]⁺:481.1376; measured: 481.1374 (0.42).

Method 2.

Compound D7.HBr (4.25 grams, 10.8 mmol), methyl chloroacetate (2.62grams, 23.9 mmol), and potassium carbonate (1.78 grams, 12.9 mmol) werestirred at room temperature in 450 mL of acetone for one day. Afterthis, additional methyl chloroacetate (1.12 grams, 10.2 mmol) andpotassium carbonate (2.76 grams, 20.0 mmol) were added over 3 days whilefollowing the reaction by TLC. Insoluble material was removed by gravityfiltration and the light orange filtrate (which also exhibits intenseblue fluorescence, λ_(ex)=365 nm) was concentrated in vacuo. The residuewas briefly boiled in fresh acetone and filtered to collect a powderwhich was dried under vacuum. This afforded 0.52 grams (11%) of D2 as atan powder. Additional material (1.48 grams) of lower purity may beobtained from the filtrate. ¹H NMR (600 MHz, DMSO-d₆) δ 8.25 (s, 2H,H5), 7.54 (d, J=8.1 Hz, 2H, H4), 7.50 (t, J=8.8 Hz, 2H, H3), 7.07 (d,J=7.4 Hz, 2H, H2), 4.99 (s, 4H, OCH₂), 3.69 (s, 6H, OCH₃), 3.11 (s, 4H,ArCH₂). ¹³C NMR (150 MHz, DMSO-d₆) δ 169.3 (C═O), 153.0 (C), 150.4 (C),138.5 (C), 135.0 (CH), 133.2 (C), 129.2 (C), 127.6 (CH), 120.0 (CH),109.5 (CH), 65.1 (CH₂), 52.0 (OCH₃), 27.1 (ArCH₂). IR (KBr) 3360 (m),2949 (m), 1751 (s), 1606 (m), 1441 (s), 1241 (s), 1111 (s), 760 (s).

Example 3

Crude compound D2 (0.10 grams, 0.22 mmol) was dissolved in 11 mL ofmethanol, and then lithium hydroxide (0.12 grams, 2.9 mmol) was addedand stirred at room temperature for four days. The resulting mixture wasvacuum filtered on a Hirsh funnel and washed with cold methanol. Thisgave 58 mg of Li₂.D3 as a yellow powder. ¹H NMR (600 MHz, DMSO) δ 8.41(s, 2H, H5), 7.55-7.65 (m, 4H, H3, H4), 7.28 (br m, 2H, H2), 4.7-4.9 (brm, 4H, OCH₂), 3.33 (s, 4H, CH₂).

Example 4

8,8′-Dimethoxy-2,2′-biquinoline (B3) was prepared according to thefollowing scheme:

Aminobenzaldehyde 1 (1.51 grams, 10.0 mmol), 2,3-butadione 3 (0.43grams, 4.96 mmol), and potassium hydroxide (0.59 grams, 11 mmol) wererefluxed in 36 mL of absolute ethanol for six days, adding more 3 (0.43grams, 4.9 mmol) in short increments during this time. The solution wasallowed to cool to room temperature and 4 mL of TFA was added understrong stirring, then the solution was stored at −12° C. for two days.Next, the precipitated product was collected by vacuum filtration andwashed consecutively with ice-cold ethanol and ether. After drying, aTFA salt of compound B3 (1.61 g, 39%) was obtained as brown, shinyflakes. ¹H NMR (600 MHz, DMSO-d₆) δ 8.77 (d, J=Hz, 2H), 8.51 (d, J=Hz,2H), 7.58 (m, 4H), 7.28 (m, 2H), 4.06 (s, 6H).

Example 5

5,5′-Dibromo-8,8′-dimethoxy-3,3′-dimethylene-2,2′-biquinoline (D4) wasprepared according to the following scheme:

First, 6-bromo-3-methoxybenzaldehyde (5) was prepared. m-Anisaldehyde(20.03 grams, 0.15 mol), NBS (28.92 grams, 0.16 mol) and 200 mL ofanhydrous DMF were stirred for 22 hours at room temperature undernitrogen in a flame-dried round-bottomed flask. The resulting orangesolution was carefully poured into 1.5 L of water, being vigorouslystirred, in order to precipitate the product. The mixture was stirredfor an additional 15 minutes, vacuum filtered, washed with water, anddried under vacuum. This gave 26.00 grams (82%) of compound 5 as a whitepowder. This product is completely pure by NMR spectroscopy and may beused in the next step, but it can be recrystallized in methyl ethylketone. After storing the solution at 0° C. for several days, theproduct crystallizes as white needles, mp 71.8-72.6° C. ¹H NMR (600 MHz,CDCl₃) δ 3.84 (s, 3H, OCH₃), 7.03 (dd, J=8.8 Hz, J′=3.2 Hz, 1H, H4),7.41 (d, J=3.0 Hz, 1H, H2), 7.52 (d, J=8.8 Hz, 1H, H5), 10.31 (s, 1H,CHO). ¹³C NMR (150 MHz, CDCl₃) δ 55.9 (OCH₃), 112.7 (CH), 118.2 (C),123.4 (CH), 134.0 (C), 134.7 (CH), 159.4 (C), 192.0 (C═O), IR (KBr,cm⁻¹) 2843 (m), 2746 (m), 1677 (s), 1598 (s), 1571 (s), 1474 (s), 1278(s), 1243 (s), 1060 (s).

Next, 6-bromo-2-nitro-3-methoxybenzaldehyde (6) was prepared. Theintermediate 5 (10.07 grams, 46.8 mmol) in powder form was added over 6minutes to a solution of 70% nitric acid (50 mL) and concentratedsulfuric acid (20 mL) cooled in an ice water-bath to 0° C. with strongstirring. The yellow mixture was allowed to cool to 10° C. and thenstirred at room temperature for an additional 29 minutes. The mixturewas poured into 350 mL of ice-water, vacuum filtered, washed withice-water (20 mL). The crude powder collected (9.34 grams, yellowpowder) was recrystallized from toluene several times. This gave 8.24grams (68%) of nitro derivative 6 as light yellow crystals, mp164.2-165.2° C. ¹H NMR (600 MHz, CDCl₃) δ 3.93 (s, 3H, OCH₃), 7.19 (d,J=9.0 Hz, 1H, H4), 7.74 (d, J=9.1 Hz, 1H, H5), 10.25 (s, 1H, CHO). ¹³CNMR (150 MHz, CDCl₃) δ 57.2 (OCH₃), 116.4 (C), 119.3 (CH), 125.3 (C),136.2 (CH), 140.0 (C), 150.7 (C), 188.5 (C═O). IR (KBr) 2849 (w), 2768(w), 1705 (s), 1593 (s), 1548 (s), 1466 (s), 1367 (s), 1228 (s), 1082(s), 647 (s). HRMS, M+Na⁺ (abundance/ppm); calculated for[C₈H₆BrNNaO₄]⁺: 281.9378; measured: 281.9373 (1.8).

Then, 2-amino-6-bromo-3-methoxybenzaldehyde (7) was prepared. Crystalsof compound 6 (2.2 grams, 8.6 mmol) were pulverized using a mortar andadded to a 3-necked, 3-L round bottomed flask equipped with an Allihncondenser, a thermometer, and a mechanical stirrer. Next, sodiumbisulfite (35.87 grams, 0.34 mol) was added followed by 1.5 L of water.The mixture was vigorously stirred and heated to boiling point using aBunsen burner in order to obtain a solution (light yellow-green color).This solution was allowed to cool down to room temperature,iron(II)sulfate heptahydrate (20.1 grams, 72.3 mmol) was added, and thesolution was stirred for 5 minutes until it all dissolved. The resultingorange solution was heated to boiling point over 26 minutes using aBunsen burner, upon which it turned cloudy. The resulting mixture wasallowed to cool down below boiling point (ca. 7 minutes) and then to itwas carefully and slowly added 200 mL of saturated aqueous sodiumbicarbonate through the condenser under vigorous stirring. The newmixture was heated to boiling point under a flame over 14 minutes, whenit turned brown. The mixture was immediately vacuum filtered into afilter flask immersed in an ice-water bath. The iron hydroxide byproductcollected was dried under aspirator pressure and washed with ether(4×200 mL). Each of these fractions was subsequently used to extract thefiltrate, which contains some crystallized product. The combined organiclayers were dried over anhydrous sodium sulfate, gravity filtered, andthe solvent removed in a rotavap. After drying under reduced pressureover drierite, 1.40 grams (71%) of product 7 was obtained as an orangepowder, mp 73.8-74.4° C. ¹H NMR (600 MHz, DMSO-d₆) δ 3.83 (s, 3H, OCH₃),6.81 (d, J=8.4 Hz, 1H, H4), 6.89 (d, J=8.2 Hz, 1H, H5), 7.39 (br s, 2H,NH2, 10.19 (s, 1H, CHO). ¹³C NMR (150 MHz, CDCl₃) δ 56.0 (OCH₃), 113.8(CH), 113.9 (C), 118.5 (C), 119.2 (CH), 143.8 (C), 146.7 (C), 195.6(C═O). IR (KBr) 3419 (s), 3306 (s), 2872 (w), 2776 (w), 1648 (s), 1622(s), 1579 (s), 1553 (s), 1459 (s), 1246 (s), 1052 (m), 664 (w). HRMS,M+H⁺ (abundance/ppm); calculated for [C₈H₆BrNO₂]⁺: 229.9817; measured:229.9812 (2.2).

5,5′-Dibromo-8,8′-dimethoxy-3,3′-dimethylene-2,2′-biquinoline (D4) wasthen prepared. 1,2-Cyclohexadienone (0.12 grams, 1.1 mmol),2-amino-6-bromo-3-methoxybenzaldehyde 7 (0.51 grams, 2.2 mmol),potassium hydroxide (0.032 grams, 0.6 mmol), and 25 mL of absoluteethanol were stirred under nitrogen in a flame dried round-bottomedflask equipped with a condenser until a yellow solution was obtained.This was kept in reflux for 25 hours. Part of the product precipitatedand was collected by vacuum filtration to afford 0.30 grams of lightolive green flakes. The filtrate was concentrated in vacuo and treatedwith 5 mL of TFA and then 15 L of ethanol to precipitate the product.After cooling and vacuum filtration, 0.17 grams of a bright red powderwas obtained. Both product samples were combined, added 150 mL ofchloroform and washed with a 0.03 M aqueous solution oftris(hydroxymethyl) aminomethane (2×45 mL), brine (45 mL), dried overmagnesium sulfate, filtered, and the solvent removed in a rotavap. Afterdrying under reduced pressure over drierite, 0.41 grams (76%) of a lightyellow powder was collected. The compound is sufficiently pure forfurther reactions but if desired it can be recrystallized fromchloroform and hexane and stored at 2° C. to induce crystallization.This gave 0.13 grams (25%) of compound D4 as yellow needles. ¹H NMR (600MHz, CDCl₃) δ 8.36 (s, 2H, H5), 7.72 (d, J=8.2 Hz, 2H, H3), 6.91 (d,J=8.3 Hz, 2H, H2), 4.13 (s, 3H, OCH₃), 3.32 (s, 4H, ArCH₂). ¹³C NMR (150MHz, CDCl₃) δ 156.2 (C), 151.3 (C), 141.0 (C), 134.6 (C), 134.4 (CH),131.1 (CH), 128.4 (C), 111.0 (C), 107.9 (CH), 56.0 (OCH₃), 28.6 (CH₂).IR (KBr) 3418.8 (s), 3306.4 (s), 1648.0 (s), 1578.7.5 (s), 1553.0 (s),1245.9 (s), 1052.3 (m), 663.9 (w). HRMS, M+H⁺ (abundance/ppm);calculated for [C₁₆H₂₂Br₂N₂NaO₂]⁺: 520.9476; measured: 520.9490 (2.7).

Example 6

2,6-bis[8-(methoxycarbonylmethoxy)quinolin-2-yl]pyridine (L1) wasprepared according to the following scheme:

Scaffold H2 was prepared according to the literature. H2 is2,6-bis[8-hydroxyquinolin-2-yl] pyridine.

Scaffold H2 (0.12 grams, 0.32 mmol), cesium carbonate (0.32 grams, 0.97mmol), and methyl chloroacetate (77 milligrams, 0.71 mmol) were stirredat room temperature in 10 mL of anhydrous DMF for 2 days. The mixturewas vacuum filtered, washed with DMF (2×3 mL), and the filtrate wasconcentrated in vacuo and dried under vacuum The crude light brownpowder collected (0.17 grams) was heated to boiling point in 25 mL oftoluene and gravity filtered to remove insoluble particles, which werewashed with 5 mL of boiling toluene. The product crystallized as verypale orange-white short needles (81 mg, 50%) from the filtrate after itwas stored at −2° C. for 3 days. A second crop (27 mg, 17%) of a tanpowder was obtained after partial concentration of the filtrate to 10 mLand storing the solution at −11° C. for 2 days. ¹H NMR (800 MHz,DMSO-d₆) δ 8.94 (d, J=8.5 Hz, 2H, H5), 8.76 (d, J=7.7 Hz, 2H, H7), 8.61(d, J=8.5 Hz, 2H, H6), 8.31 (t, J=7.7 Hz, 1H, H8), 7.70 (d, J=8.0 Hz,2H, H4), 7.59 (t, J=7.8 Hz, 2H, H3), 7.25 (d, J=7.7 Hz, 2H, H2), 5.21(s, 4H, CH₂), 3.80 (s, 6H, OCH₃). ¹H NMR (600 MHz, CDCl₃) δ 8.88 (d,J=8.5 Hz, 2H, H5), 8.80 (d, J=7.7 Hz, 2H, H7), 8.31 (d, J=8.5 Hz, 2H,H6), 8.06 (t, J=7.7 Hz, 1H, H8), 7.54 (d, J=8.1 Hz, 2H, H4), 7.46 (t,J=7.8 Hz, 2H, H3), 7.13 (d, J=7.5 Hz, 2H, H2), 5.09 (s, 4H, CH₂), 3.87(s, 6H, OCH₃). ¹³C NMR (150 MHz, CDCl₃) δ 169.8 (C═O), 155.5 (2×C),154.1 (C), 140.2 (C), 138.2 (CH), 137.0 (CH), 129.9 (C), 126.9 (CH),122.6 (CH), 121.6 (CH), 119.8 (CH), 112.1 (CH), 67.4 (CH₂), 52.5 (CH₃).HRMS, M+Na⁺ (abundance/ppm); calculated for [C₂₉H₂₃N₃NaO₆]⁺: 532.1485;measured: 532.1459 (4.9).

Example 7

2,6-bis[8-(acetoxy)quinolin-2-yl]pyridine (L2) was prepared according tothe following scheme:

Scaffold H2 (0.30 grams, 0.83 mmol), acetyl chloride (0.58 grams, 7.4mmol), and pyridine (0.59 grams, 7.4 mmol) were stirred at roomtemperature in dichloromethane for 2 days. The solution was sequentiallywashed with 10% hydrochloric acid (3×70 mL), dilute aqueous sodiumbicarbonate (3×70 mL), and brine (1×100 mL). After drying the sampleover anhydrous sodium sulfate, solvent removal at a rotavap, and dryingunder reduced pressure for 2 days, 0.35 grams (94%) of a beige powder(L2) was obtained. Some X-ray quality crystals were obtained bydissolving a portion of the crude in a mixture of acetonitrile,methanol, and ethyl acetate and allowing it to evaporate slowly. Thecrystal structure is shown below. ¹H NMR (600 MHz, CDCl₃) δ 8.87 (d,J=8.6 Hz, 2H, H5), 8.64 (d, J=7.8 Hz, 2H, H7), 8.35 (d, J=8.6 Hz, 2H,H6), 8.02 (t, J=7.8 Hz, 1H, H8), 7.78 (d, J=8.1 Hz, 2H, H4), 7.55 (t,J=7.7 Hz, J′=7.9 Hz, 2H, H3), 7.48 (d, J=7.4 Hz, 2H, H2), 2.62 (s, 6H,CH₃). ¹³C NMR (150 MHz, CDCl₃) δ 170.0 (C═O), 156.0 (C), 155.3 (C),148.0 (C), 140.7 (C), 138.0 (CH), 137.1 (CH), 129.8 (C), 126.7 (CH),126.0 (CH), 122.4 (CH), 121.7 (CH), 119.9 (CH), 21.3 (CH₃). HRMS, M+Na⁺(abundance/ppm), Calculated for [C₂₇H₁₉N₃NaO₄]⁺: 472.1273, measured:472.1257 (3.4).

Example 8

2,6-bis[8-((2R)-2-trifluoromethyl-2-methoxy-2-phenylacetoxy)quinolin-2-yl]pyridine (L3) was prepared according to the following scheme:

Scaffold H2 (0.23 grams, 0.62 mmol), DMAP (4-dimethylaminopyridine) (14milligrams, 0.11 mmol), and DCC (N,N′-Dicyclohexylcarbodiimide) (0.29grams, 1.4 mmol) were added to 10 mL of dry dichloromethane and stirredat room temperature under nitrogen in a 3-necked round-bottomed flaskequipped with a rubber stopper, glass stopper, and a condenser with agas inlet attached. To this suspension was added (R)-Mosher's acid(α-methoxy-α-trifluoromethylphenylacetic acid) (0.33 grams, 1.4 mmol) in3 mL of dichloromethane via syringe. The syringe was rinsed withdichloromethane (2×4 mL) and the suspension stirred at room temperature.After 3 days, 5 mL of dry chloroform was added. After an additional 4days, the mixture was filtered, washed with dichloromethane (3×3 mL),and the filtrate was concentrated in vacuo, and dried under vacuum. Thecrude sample (0.63 grams) was treated with DMAP (13 mg, 0.11 mmol), DCC(0.11 grams, 0.53 mmol), (R)-Mosher's acid (0.10 grams, 0.43 mmol), and15 mL of dry dichloromethane as before for 3 days. The suspension wasvacuum filtered, washed with dichloromethane (3×5 mL). The filtrate wasdiluted with 40 mL of dichloromethane, washed with water (2×10 mL),dried over anhydrous sodium sulfate, gravity filtered, and concentrated.This crude product (0.76 grams) was recrystallized from 6 mL of toluene.This gave compound L3 as short, white needles (0.36 grams, 73%). ¹H NMR(800 MHz, DMSO-d₆) δ 8.96 (d, J=8.6 Hz, 2H, H5 or H6), 8.78 (d, J=8.6Hz, 2H, H6 or H5), 8.37 (d, J=7.6 Hz, 2H, H7), 8.17 (dd, J=7.2 Hz,J′=1.6 Hz, 2H), 8.08 (t, J=7.7 Hz, 1H, H8), 7.90 (d, J=7.5 Hz, 4H),7.77-7.82 (m, 4H), 7.67-7.59 (m, 6H). ¹H NMR (600 MHz, CDCl₃) δ 8.82 (d,J=8.6 Hz, 2H, H5 or H6), 8.37 (d, J=7.8 Hz, 2H, H7), 8.34 (d, J=8.6 Hz,2H, H6 or H5), 7.97 (d, J=7.5 Hz, 4H, H9), 7.82 (d, J=8.1 Hz, 2H, H4),7.70 (t, J=7.8 Hz, 1H, H8), 7.56 (t, J=7.7 Hz, J′=7.9 Hz, 2H, H3),7.44-7.52 (m, 8H, H2, H10, H11), 3.92 (s, 6H, OCH₃). ¹³C NMR (150 MHz,CDCl₃) δ 165.4 (C═O), 156.7 (C), 155.3 (C), 147.0 (C), 140.5 (C), 137.8(CH), 137.1 (CH), 132.1 (C), 130.1 (CH), 129.9 (C), 128.8 (CH), 128.2(CH), 126.9 (CH), 126.5 (CH), 126.5 (CF₃), 124.6 (CF₃), 122.8 (CH),122.7 (CF₃), 121.6 (CH), 120.8 (CF₃), 120.3 (CH), 85.7 (C—CF₃), 85.5(C—CF₃), 85.3 (C—CF₃), 85.1 (C—CF₃), 56.2 (CH₃). HRMS, M+Na⁺(abundance/ppm), Calculated for [C₄₃H₂₉F₆N₃NaO₆]⁺: 820.1858, Measured:820.1824 (4.1).

Example 9

8-butyl-1,15-bis(methoxycarbonylmethoxy)-diquinolino[2,3-c:3′,2′-h]-6,7,9,10-tetrahydroacridine(L4) was prepared according to the following scheme:

8-Butyl-1,15-dimethoxydiquinolino[2,3-c:3′,2′-h]-6,7,9,10-tetrahydroacridine(H4) was prepared. To a flame-dried 250 mL round bottomed flask equippedwith a condenser, stir bar, and nitrogen gas inlet and containing asolution of potassium hydroxide (0.16 grams, 2.8 mmol) in 25 mL ofabsolute ethanol was added diketone H3 (1.87 grams, 6.9 mmol) dissolvedin 10 mL of absolute ethanol followed by aminoaldehyde 1 in 10 mL ofabsolute ethanol. Reactant containers were rinsed with an additional 50mL of ethanol and the resulting brown solution was kept in reflux undernitrogen for 7 days. Potassium hydroxide was added in small portionsduring this period and the reaction monitored by TLC (silica gel;acetonitrile:ammonium hydroxide; 9:1; v/v) until all the aminoaldehydehad been consumed. The total amount of potassium hydroxide used was 2.18grams (0.039 mol). The solution was concentrated in vacuo and to theoily residue was added 11 mL of TFA, which produced a precipitate. Thewhole sample was dissolved using chloroform (100 mL) and methanol (25mL) and washed with water (4×100 mL). Additional chloroform and methanolwas used to help dissolve any precipitate that formed during the washingprocess. The organic layer was then washed with aqueous 0.08 Mtris(hydroxymethyl)aminomethane (2×100 mL), dried over a mixture ofsodium sulfate and magnesium sulfate. Upon filtration, solvent removalin a rotavap, and overnight drying under reduced pressure 4.39 grams ofneutral product H4 was collected. This product contained some impuritiesbut the sample was sufficiently pure so as to be used immediately forthe next step. ¹H NMR (600 MHz, TFA-d) δ 8.97 (s, 2H, H5), 7.94 (t,J=8.2 Hz, J′=8.0 Hz, 2H, H3), 7.81 (d, J=8.3 Hz, 2H, H4), 7.61 (d, J7.8=Hz, 2H, H2), 4.37 (s, 6H, OCH₃), 3.4-3.6 (m, 8H, ring CH₂CH₂), 3.02(br t, J=7.2 Hz, 2H, ArCH₂), 1.5-1.7 (m, 4H, CH₂CH₂), 1.05 (t, J=6.9 Hz,3H, CH₃).

Next,8-butyl-bis(quinoline-1,15-diol)[2,3-c:3′,2′-h]-6,7,9,10-tetrahydroacridine(H5) was prepared. Crude compound H4 (1.13 grams, 2.25 mmol) was boiledin 90 mL of 48% aqueous hydrobromic acid for 29 hours and allowed tocool to room temperature overnight. The crystallized product wascollected by vacuum filtration, washed with water (2×5 mL), and driedunder reduced pressure overnight to give a brown powder. ¹H NMR (800MHz, TFA-d) δ 9.08 (s, 2H, H5),), 8.00 (t, J=7.9 Hz, 2H, H3), 7.94 (d,J=8.2 Hz, 2H, H4), 7.86 (d, J=7.6 Hz, 2H, H2), 3.71 (m, 2H, CH₂), 3.67(m, 2H, CH₂), 3.19 (br t, J=7.8 Hz, J′=8.3 Hz, 2H, ArCH₂), 1.82 (m, 2H,CH₂), 1.78 (m, 2H, CH₂), 1.20 (t, J=7.2 Hz, 3H, CH₃). ¹³C NMR (150 MHz,TFA-d) δ 156.1 (C), 148.0 (C), 147.8 (CH), 146.1 (C), 143.8 (C), 143.0(C), 134.3 (C), 134.0 (CH), 132.6 (C), 130.4 (C), 122.2 (CH), 120.9(CH), 32.8 (CH₂), 30.5 (CH₂), 26.9 (CH₂), 25.1 (CH₂), 24.6 (CH₂), 14.2(CH₃).

The resulting brown powder (0.88 grams) was dissolved in 200 mL ofchloroform and 15 mL of methanol and washed with 0.07 Mtris(hydroxymethyl)aminomethane (2×75 mL), brine (75 mL), dried overmagnesium sulfate, filtered, the solvent removed in a rotavap, and theresidue dried under vacuum. This gave 0.66 grams (62%) of H5 as a brownsolid sample. ¹H NMR (250 MHz, DMSO-d₆) δ 11.25 (br s, OH), 8.21 (s, 2H,H5), 7.45 (d, J=7.8 Hz, 2H, H3), 7.34 (d, J=7.8 Hz, 2H, H4), 7.05 (d,J=7.5 Hz, 2H, H2), 3.16 (br s, 8H, CH₂CH₂), 2.86 (m, 2H, ArCH₂), 1.51(m, 4H, CH₂CH₂), 0.98 (t, J=6.8 Hz, 3H, CH₃).

Crude compound H5 (0.26 grams, 0.55 mmol), cesium carbonate (0.18 grams,0.56 mmol), and methyl chloroacetate (0.12 grams, 1.1 mmol) were stirredunder nitrogen at room temperature in 25 mL of anhydrous DMF for oneday. Additional drops of methyl chloroacetate were added at intervalsuntil H5 was fully consumed as determined by TLC (silica gel,MeCN:NH₄OH, 9:1, v/v). The mixture was then vacuum filtered, washed with10 mL of a hexane/chloroform solution (9:1, v/v), then with 5 mL ofhexane. The filtrate was concentrated in vacuo to give a brown powder(0.25 grams, 75%). The crude can be recrystallized from methanol/ethylacetate to afford the product L4 as light orange needles. ¹H NMR (600MHz, TFA-d) δ 9.04 (s, 2H, H5), 7.9-8.0 (m, 4H, H3, H4), 7.69 (d, J=7.4Hz), 2H, H2), 5.22 (s, 4H, CH₂), 3.73 (s, 6H, OCH₃), 3.50-3.65 (m, 8H,ring CH₂CH₂), 3.07 (br t, J=7.3 Hz, J′=7.6 Hz, 2H, ArCH₂), 1.55-1.75 (m,4H, CH₂CH₂), 1.07 (t, J=7.1 Hz, J′=6.8 Hz, 3H, CH₃). HRMS, M+Na⁺(abundance/ppm); calculated for [C₃₇H₃₅N₃NaO₆]⁺: 640.2424; measured:640.2417 (1.1).

Example 10

Representative complexes of8,8′-dimethoxy-3,3′-dimethylene-2,2′-biquinoline (D1) were made insolution to obtain NMR spectra.

The following ¹H NMR spectra were obtained by preparing complexes insitu as follows: 100 μL of the corresponding metal salt in D₂O was addedto a solution of D1 in CD₃CN (0.5 mL), and then mixed to obtain onephase. Final concentrations: [D1]=0.005 M; [M⁺]=0.05 M (perchloratesalts). Each spectrum was referenced to the middle peak of residualCH₃CN (1.94 ppm).

D1+NaClO₄. ¹H NMR (800 MHz, CD₃CN/D₂O, 0.5:0.01 v/v) δ 3.27 (s, 4H,CH₂), 4.07 (s, 6H, OCH₃), 7.20 (d, 2H, H2), 7.55 (d, 2H, H4), 7.51 (t,2H, H3), 8.24 (s, 2H, H5).

D1+AgClO₄. ¹H NMR (800 MHz, CD₃CN/D₂O, 0.5:0.01 v/v) δ 3.22 (s, 4H,CH₂), 4.11 (s, 6H, OCH₃), 7.24 (d, 2H, H2), 7.49 (d, 2H, H4), 7.58 (t,2H, H3), 8.26 (s, 2H, H5). This complex is shown in FIG. 9.

D1+Ca(ClO₄)₂. ¹H NMR (800 MHz, CD₃CN/D₂O, 0.5:0.01 v/v) δ 3.34 (s, 4H,CH₂), 4.26 (s, 6H, OCH₃), 7.39 (d, 2H, H2), 7.64 (d, 2H, H4), 7.66 (t,2H, H3), 8.41 (s, 2H, H5). This complex is shown in FIG. 10.

D1+Zn(ClO₄)₂. The following is the data for the 1:1 complex. ¹H NMR (800MHz, CD₃CN/D₂O, 0.5:0.01 v/v) δ 3.43 (s, 4H, CH₂), 4.20 (s, 6H, OCH₃),7.41 (d, 2H, H2), 7.68 (d, 2H, H4), 7.74 (t, 2H, H3), 8.63 (s, 2H, H5).The 2:1 (D₁:Zn²⁺) complex is also present in the solution, albeit intrace amount, and gives this data: δ 2.97 (s, 6H, OCH₃), 3.63 (s, 4H,CH₂), 6.96 (d, 2H, H2), 7.57 (t, 2H, H3), 7.70 (d, 2H, H4), 8.84 (s, 2H,H5). The 2:1 encapsulating complex is shown in FIG. 11.

D1+Al(ClO₄)₃. ¹H NMR (800 MHz, CD₃CN/D₂O, 0.5:0.01 v/v) δ 3.39 (s, 4H,CH₂), 4.19 (s, 6H, OCH₃), 7.41 (d, 2H, H2), 7.62 (d, 2H, H4), 7.73 (t,2H, H3), 8.64 (s, 2H, H5). Crystallization of this sample unexpectedlyafforded the protonated compound shown in FIG. 15.

D1+La(ClO₄)₃. ¹H NMR (800 MHz, CD₃CN/D₂O, 0.5:0.01 v/v) δ 3.27 (br s,4H, CH₂), 4.11 (br s, 6H, OCH₃), 7.25 (br s, 2H, H2), 7.53 (br s, 2H),7.63 (br s, 2H), 8.33 (br s, 2H, H5).

(b) The following is the ¹H NMR spectra obtained after dissolvingcrystals of the complex in the indicated NMR solvent. The barium complexwas too insoluble for analysis. Nickel and copper complexes gave severalcomplexes in solution (with broad signals), which complicated NMRanalysis.

D1+KO—CO—CH₃. ¹H NMR (600 MHz, CD₃CN) δ 3.12 (s, 4H, CH₂), 3.87 (br s,6H, OCH₃), 7.00 (d, 2H, H2), 7.42 (d, 2H, H4), 7.49 (t, 2H, H3), 8.10(s, 2H, H5).

D1+Mg(ClO₄)₂. ¹H NMR (600 MHz, CD₃CN) δ 3.27 (s, 4H, CH₂), 4.24 (s, 6H,OCH₃), 7.35 (br d, 2H, H2), 7.61 (br d, 2H, H4), 7.68 (br t, 2H, H3),8.41 (br s, 2H, H5).

D1+Cd(ClO₄)₂. This is a 2:1 encapsulating complex. ¹H NMR (600 MHz,CD₃CN) δ 2.97 (s, 6H, OCH₃), 3.61 (s, 4H, CH₂), 7.04 (d, 2H, H2), 7.61(t, 2H, H4), 7.72 (d, 2H, H3), 8.79 (s, 2H, H5). This complex is shownin FIG. 12.

D1+Hg(ClO₄)₂. This is a 2:1 encapsulating complex. ¹H NMR (600 MHz,CD₃CN) δ 2.92 (s, 6H, OCH₃), 3.60 (s, 4H, CH₂), 7.01 (d, 2H, H2), 7.64(t, 2H, H4), 7.72 (d, 2H, H3), 8.81 (s, 2H, H5). This complex is shownin FIG. 13.

D1+AgClO₄. ¹H NMR (800 MHz, CD₃CN) δ 3.30 (s, 4H, CH₂), 3.98 (s, 6H,OCH₃), 7.22 (br d, 2H, H2), 7.54 (d, 2H, H4), 7.61 (t, 2H, H3), 8.26 (s,2H, H5).

D1+Pb(ClO₄)₂. ¹H NMR (600 MHz, CD₃CN) δ 3.44 (s, 4H, CH₂), 4.38 (s, 6H,OCH₃), 7.50 (d, 2H, H2), 7.74 (d, 2H, H4), 7.80 (t, 2H, H3), 8.69 (s,2H, H5). This complex is shown in FIG. 14.

D1+La(ClO₄)₃. ¹H NMR (600 MHz, CD₃CN) δ 3.45 (s, 4H, CH₂), 4.24 (s, 6H,OCH₃), 7.43 (d, 2H, H2), 7.64 (d, 2H, H4), 7.77 (t, 2H, H3), 8.67 (s,2H, H5).

D1+Eu(ClO₄)₂. ¹H NMR (600 MHz, CD₃CN) δ 3.45 (s, 4H, CH₂), 4.24 (s, 6H,OCH₃), 7.44 (d, 2H, H2), 7.66 (d, 2H, H4), 7.79 (t, 2H, H3), 8.68 (s,2H, H5).

D1+Gd(ClO₄)₃. ¹H NMR (600 MHz, CD₃CN) δ 3.41 (br s, 4H, CH₂), 4.20 (brs, 6H, OCH₃), 7.39 (br s, 2H, H2), 7.60 (br s, 2H), 7.72 (br s, 2H),8.57 (br s, 2H, H5).

FIG. 15 is an illustration of the crystal structure of the complexD1.HClO₄, and as noted above was unexpectedly crystallized from aluminumperchlorate.

The present disclosure has been described with reference to exemplaryembodiments. Obviously, modifications and alterations will occur toothers upon reading and understanding the preceding detaileddescription. It is intended that the present disclosure be construed asincluding all such modifications and alterations insofar as they comewithin the scope of the appended claims or the equivalents thereof.

The invention claimed is:
 1. A compound having the structure of Formula(S1), or a polymer formed from a monomer having the structure of Formula(S1):

wherein R₁, R₂, R₃, R₅, R₆, R₇, R₈, R₁₀, R₁₁, and R₁₂ are independentlyselected from hydrogen, halogen, alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, hydroxyl, aldehyde,carboxy, ester, sulfonate, sulfonamide, carboxamide, amino, nitro,nitroso, nitrile, azo, and a water-solubilizing group, with the provisothat one of R₁, R₂, R₃, and R₅ is —OR′, —SR′, or —NR′₂, and the provisothat one of R₈, R₁₀, R₁₁, and R₁₂ is —OR″, —SR″, or —NR″₂; and whereinR′ and R″ either (a) are independently selected from hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, or a chelating ligand comprising at least one linking groupand at least one heteroatom, or (b) together form a linking moiety thatcontains at least one heteroatom, so that the compound is a macrocycliccompound; and wherein R₄ and R₉ are the same, and are halogen, aryl,substituted aryl, alkynyl, or substituted alkynyl.
 2. The compound orpolymer of claim 1, wherein R′ and R″ are each a chelating ligandcomprising at least one linking group and at least one heteroatom, andwherein each chelating ligand is selected from —(CH₂)_(n)—CO—OR,—(CH₂)_(n)—CO—NR¹R², —(CH₂)_(n)—Z—(CH₂)_(m)—CO—OR,—(CH₂)_(n)—NR³—(CH₂)_(m)—CO—OR, —(CH₂)_(n)—[O—(CH₂)_(k)]_(m)—OR, orsalts thereof; wherein k, m, and n are independently integers from 1 to10; R, R¹, R², and R³ are independently hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;and Z is sulfur or oxygen.
 3. The compound or polymer of claim 1,wherein R′ and R″ are the same.
 4. The compound or polymer of claim 1,wherein R′ and R″ are different.
 5. A compound having the structure ofone of formulas D1, D2, D3, D4, D5, D6, D7, D8, or D9, or a polymerformed from a monomer having the structure of one of formulas D1, D2,D3, D4, D5, D6, D7, D8, or D9:

wherein R^(a) and R^(b) are independently alkyl, substituted alkyl,aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R′ and R″are independently alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, or a chelating ligand comprising atleast one linking group and at least one heteroatom; X₁ and X₂ areindependently halogen; and Ar₁ and Ar₂ are independently aryl orsubstituted aryl.
 6. A compound having the structure of one of formulasS1-M, M1, M2, M3, M4, M5, M6, or M7, or a polymer formed from a monomerhaving the structure of one of formulas S1-M, M1, M2, M3, M4, M5, M6, orM7:

wherein p, q, and t are independently integers from 1 to 10; Z is oxygenor sulfur; L′ and L″ are independently O, S, or NR′; R′, R₁₃, and R₁₄are independently hydrogen, alkyl, substituted alkyl, aryl, orsubstituted aryl; L is a linking group; and wherein R₂, R₃, R₄, R₅, R₆,R₇, R₈, R₉, R₁₀, and R₁₁ are independently selected from hydrogen,halogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, hydroxyl, aldehyde, carboxy, ester, sulfonate,sulfonamide, carboxamide, amino, nitro, nitroso, nitrile, azo, and awater-solubilizing group.
 7. A method for making a compound of Formula(S1), D1, D2, D3, D4, D5, D6, D7, D8, D9, S1-M, M1, M2, M3, M4, M5, M6,or M7:

wherein for Formula (S1) R₁, R₂, R₃, R₅, R₆, R₇, R₈, R₁₀, R₁₁, and R₁₂are independently selected from hydrogen, halogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, hydroxyl,aldehyde, carboxy, ester, sulfonate, sulfonamide, carboxamide, amino,nitro, nitroso, nitrile, azo, and a water-solubilizing group, with theproviso that one of R₁, R₂, R₃, and R₅ is —OR′, —SR′, or —NR′₂, and theproviso that one of R₈, R₁₀, R₁₁, and R₁₂ is —OR″, —SR″, or —NR″₂; andwherein R′ and R″ either (a) are independently selected from hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, or a chelating ligand comprising at least onelinking group and at least one heteroatom, or (b) together form alinking moiety that contains at least one heteroatom, so that thecompound is a macrocyclic compound; and wherein R₄ and R₉ are the same,and are halogen, aryl, substituted aryl, alkynyl, or substitutedalkynyl;

wherein for Formula D1, D2, D3, D4, D5, D6, D7, D8, and D9, R^(a) andR^(b) are independently alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, or substituted heteroaryl; R′ and R″ are independentlyalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, or a chelating ligand comprising at least onelinking group and at least one heteroatom; X₁ and X₂ are independentlyhalogen; and Ar₁ and Ar₂ are independently aryl or substituted aryl;

wherein p, q, and t are independently integers from 1 to 10; Z is oxygenor sulfur; L′ and L″ are independently O, S, or NR′; R′, R₁₃, and R₁₄are independently hydrogen, alkyl, substituted alkyl, aryl, orsubstituted aryl; L is a linking group; and wherein for Formula S1-M,M1, M2, M3, M5, and M6, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, and R₁₁ areindependently selected from hydrogen, halogen, alkyl, substituted alkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, hydroxyl, aldehyde,carboxy, ester, sulfonate, sulfonamide, carboxamide, amino, nitro,nitroso, nitrile, azo, and a water-solubilizing group; the processcomprising: reacting a 1,2-cyclohexanedione of Formula (S1a) with afirst aminoaldehyde containing an —OR^(a), —SR^(a), or —NR^(a) ₂ group,wherein R^(a) is hydrogen or alkyl, to obtain a resulting compound; and

 optionally, when R′ and R″ are different, reacting the resultingcompound with a second different aminoaldehyde containing an —OR^(b),—SR^(b), or —NR^(b) ₂ group, wherein R^(b) is hydrogen or alkyl.
 8. Themethod of claim 7, wherein the reacting occurs in the presence ofpotassium hydroxide and ethanol until the first aminoaldehyde isconsumed, wherein trifluoroacetic acid is subsequently added todehydrate and precipitate the compound of Formula (S1).
 9. The method ofclaim 7, wherein R′ and R″ are different, wherein R^(a) and R^(b) areboth —CH₃, and further comprising: reducing the resulting compoundcontaining R^(a) and R^(b) with hydrobromic acid to form a di(hydroxy,thio, or amino)-3,3′-dimethylene-2,2′-biquinoline; reacting thedi(hydroxy, thio, or amino)-3,3′-dimethylene-2,2′-biquinoline with afirst reactant of the formula L^(a)-R′, wherein L^(a) is a leavinggroup; and reacting the resulting compound with a second reactant of theformula L^(b)-R″, wherein L^(b) is a leaving group.
 10. The method ofclaim 9, wherein the reacting of the di(hydroxy, thio, oramino)-3,3′-dimethylene-2,2′-biquinoline with the first and secondreactants occurs in the presence of a polar solvent.
 11. A method forbinding a metal ion in a solution, comprising: adding to the solution acompound having the structure of Formula (S1), D1, D2, D3, D4, D5, D6,D7, D8, D9, S1-M, M1, M2, M3, M4, M5, M6, or M7, or a polymer formedfrom a monomer having the structure of Formula (S1), D1, D2, D3, D4, D5,D6, D7, D8, D9, S1-M, M1, M2, M3, M4, M5, M6, or M7:

wherein for Formula (S1), R₁, R₂, R₃, R₅, R₆, R₇, R₈, R₁₀, R₁₁, and R₁₂are independently selected from hydrogen, halogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, hydroxyl,aldehyde, carboxy, ester, sulfonate, sulfonamide, carboxamide, amino,nitro, nitroso, nitrile, azo, and a water-solubilizing group, with theproviso that one of R₁, R₂, R₃, and R₅ is —OR′, —SR′, or —NR′₂, and theproviso one of R₈, R₁₀, R₁₁, and R₁₂ is —OR″, —SR″, or —NR″₂; andwherein R′ and R″ either (a) are independently selected from hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, or a chelating ligand comprising at least onelinking group and at least one heteroatom, or (b) together form alinking moiety that contains at least one heteroatom, so that thecompound is a macrocyclic compound; and wherein R₄ and R₉ are the same,and are halogen, aryl, substituted aryl, alkynyl, or substitutedalkynyl;

wherein for Formula D1, D2, D3, D4, D5, D6, D7, D8, and D9, R^(a) andR^(b) are independently alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, or substituted heteroaryl; R′ and R″ are independentlyalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, or a chelating ligand comprising at least onelinking group and at least one heteroatom; X₁ and X₂ are independentlyhalogen; and Ar₁ and Ar₂ are independently aryl or substituted aryl;

wherein p, q, and t are independently integers from 1 to 10; Z is oxygenor sulfur; L′ and L″ are independently O, S, or NR′; R′, R₁₃, and R₁₄are independently hydrogen, alkyl, substituted alkyl, aryl, orsubstituted aryl; L is a linking group; and wherein for Formula S1-M,M1, M2, M3, M5, and M6, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, and R₁₁ areindependently selected from hydrogen, halogen, alkyl, substituted alkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, hydroxyl, aldehyde,carboxy, ester, sulfonate, sulfonamide, carboxamide, amino, nitro,nitroso, nitrile, azo, and a water-solubilizing group; wherein thecompound or polymer forms a complex upon binding to the metal ion. 12.The method of claim 11, further comprising monitoring the solution todetect a change in the color of light emitted by the compound orpolymer, such a change indicating that binding has occurred.
 13. Themethod of claim 11, further comprising extracting the complex from thesolution.